Modulators of YAP1 expression

ABSTRACT

The present embodiments provide methods, compounds, and compositions useful for inhibiting YAP1 expression, which may be useful for treating, preventing, or ameliorating a cancer associated with YAP1.

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is provided as a file entitledBIOL0352USSEQ_ST25.txt created Jan. 31, 2020, which is 814 kb in size.The information in the electronic format of the sequence listing isincorporated herein by reference in its entirety.

FIELD

The present embodiments provide methods, compounds, and compositionsuseful for inhibiting YAP1 expression, which can be useful for treating,preventing, or ameliorating a cancer associated with YAP1.

BACKGROUND

Yes-associated protein (YAP1) is a transcriptional coactivator that isfrequently activated in multiple human cancer types due to alterationsin the tumor suppressive ‘Hippo’ pathway or its amplification. YAP1 isthe downstream regulator of the Hippo pathway and promotes tumor growththrough both tumor autonomous and immune-regulatory mechanisms. Anactive Hippo pathway is tumor suppresive and phosphorylates YAP1,resulting in its inactivation. When the Hippo pathway is inactive, YAP1is dephosphorylated and translocated into the nucleus where it promotesexpression of multiple genes.

SUMMARY

Certain embodiments provided herein are directed to potent and tolerablecompounds and compositions useful for inhibiting YAP1 expression, whichcan be useful for treating, preventing, ameliorating, or slowingprogression of cancer associated with YAP1.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the embodiments, as claimed. Herein, the useof the singular includes the plural unless specifically statedotherwise. As used herein, the use of “or” means “and/or” unless statedotherwise. Furthermore, the use of the term “including” as well as otherforms, such as “includes” and “included”, is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in this application,including, but not limited to, patents, patent applications, articles,books, treatises, and GenBank and NCBI reference sequence records arehereby expressly incorporated by reference for the portions of thedocument discussed herein, as well as in their entirety.

It is understood that the sequence set forth in each SEQ ID NO containedherein is independent of any modification to a sugar moiety, aninternucleoside linkage, or a nucleobase. As such, compounds defined bya SEQ ID NO may comprise, independently, one or more modifications to asugar moiety, an internucleoside linkage, or a nucleobase. Compoundsdescribed by ION number indicate a combination of nucleobase sequence,chemical modification, and motif.

Unless otherwise indicated, the following terms have the followingmeanings:

“2′-deoxynucleoside” means a nucleoside comprising 2′-H(H) furanosylsugar moiety, as found in naturally occurring deoxyribonucleic acids(DNA). In certain embodiments, a 2′-deoxynucleoside may comprise amodified nucleobase or may comprise an RNA nucleobase (uracil).

“2′-O-methoxyethyl” (also 2′-MOE and 2′-O(CH₂)₂—OCH₃) refers to anO-methoxy-ethyl modification at the 2′ position of a furanosyl ring. A2′-O-methoxyethyl modified sugar is a modified sugar.

“2′-MOE nucleoside” (also 2′-O-methoxyethyl nucleoside) means anucleoside comprising a 2′-MOE modified sugar moiety.

“2′-substituted nucleoside” or “2-modified nucleoside” means anucleoside comprising a 2′-substituted or 2′-modified sugar moiety. Asused herein, “2′-substituted” or “2-modified” in reference to a sugarmoiety means a sugar moiety comprising at least one 2′-substituent groupother than H or OH.

“3′ target site” refers to the nucleotide of a target nucleic acid whichis complementary to the 3′-most nucleotide of a particular compound.

“5′ target site” refers to the nucleotide of a target nucleic acid whichis complementary to the 5′-most nucleotide of a particular compound.

“5-methylcytosine” means a cytosine with a methyl group attached to the5 position.

“About” means within ±10% of a value. For example, if it is stated, “thecompounds affected about 70% inhibition of YAP1”, it is implied thatYAP1 levels are inhibited within a range of 60% and 80%.

“Administration” or “administering” refers to routes of introducing acompound or composition provided herein to an individual to perform itsintended function. An example of a route of administration that can beused includes, but is not limited to parenteral administration, such assubcutaneous, intravenous, or intramuscular injection or infusion.

“Administered concomitantly” or “co-administration” means administrationof two or more compounds in any manner in which the pharmacologicaleffects of both are manifest in the patient. Concomitant administrationdoes not require that both compounds be administered in a singlepharmaceutical composition, in the same dosage form, by the same routeof administration, or at the same time. The effects of both compoundsneed not manifest themselves at the same time. The effects need only beoverlapping for a period of time and need not be coextensive.Concomitant administration or co-administration encompassesadministration in parallel or sequentially.

“Amelioration” refers to an improvement or lessening of at least oneindicator, sign, or symptom of an associated disease, disorder, orcondition. In certain embodiments, amelioration includes a delay orslowing in the progression or severity of one or more indicators of acondition or disease. The progression or severity of indicators may bedetermined by subjective or objective measures, which are known to thoseskilled in the art.

“Animal” refers to a human or non-human animal, including, but notlimited to, mice, rats, rabbits, dogs, cats, pigs, and non-humanprimates, including, but not limited to, monkeys and chimpanzees.

“Antibody,” as used in this disclosure, refers to an immunoglobulin or afragment or a derivative thereof, and encompasses any polypeptidecomprising an antigen-binding site, regardless of whether it is producedin vitro or in vivo. The term includes, but is not limited to,polyclonal, monoclonal, monospecific, polyspecific, non-specific,humanized, single-chain, chimeric, synthetic, recombinant, hybrid,mutated, and grafted antibodies. Unless otherwise modified by the term“intact,” as in “intact antibodies,” for the purposes of thisdisclosure, the term “antibody” also includes antibody fragments such asFab, F(ab′)2, Fv, scFv, Fd, dAb, and other antibody fragments thatretain antigen-binding function, i.e., the ability to bind, for example,CTLA-4 or PD-L1 specifically. Typically, such fragments would comprisean antigen-binding domain.

“Anti-CTLA-4 antibody” refers to an antibody or antigen binding fragmentthereof that specifically binds a CTLA-4 polypeptide. Exemplaryanti-CTLA-4 antibodies are described for example at U.S. Pat. Nos.6,682,736; 7,109,003; 7,123,281; 7,411,057; 7,824,679; 8,143,379;7,807,797; and 8,491,895 (Tremelimumab is 11.2.1, therein), which areherein incorporated by reference. Tremelimumab (U.S. Pat. No. 6,682,736)is an exemplary anti-CTLA-4 antibody. Tremelimumab VL, VH, and CDR aminoacid sequences are provided at SEQ ID NOs: 1-8, herein.

“Anti-OX40 antibody” refers to an antibody or antigen binding fragmentthereof that specifically binds OX40. OX40 antibodies include monoclonaland polyclonal antibodies that are specific for OX40 and antigen-bindingfragments thereof. In certain aspects, anti-OX40 antibodies as describedherein are monoclonal antibodies (or antigen-binding fragments thereof),e.g., murine, humanized, or fully human monoclonal antibodies. In oneparticular embodiment, the OX40 antibody is an OX40 receptor agonist,such as the mouse anti-human OX40 monoclonal antibody (9B12) describedby Weinberg et al., J Immunother 29, 575-585 (2006). In anotherembodiment, an OX40 antibody is MEDI0562 as described in US2016/0137740, incorporated herein by reference. MEDI0562 VH and VL aminoacid sequences are provided at SEQ ID NOs: 25-26, herein. In otherembodiments, the antibody which specifically binds to OX40, or anantigen-binding fragment thereof, binds to the same OX40 epitope as mAb9B12.

“Anti-PD-L1 antibody” refers to an antibody or antigen binding fragmentthereof that specifically binds a PD-L1 polypeptide. Exemplaryanti-PD-L1 antibodies are described for example at US2013/0034559, U.S.Pat. Nos. 8,779,108 and 9,493,565 which are herein incorporated byreference. Durvalumab (MEDI4736) is an exemplary anti-PD-L1 antibody.Durvalumab VL, VH, and CDR amino acid sequences are provided at SEQ IDNOs: 9-16, herein. Other anti-PD-L1 antibodies include BMS-936559(Bristol-Myers Squibb) and MPDL3280A (atezolizumab) (Roche).

“Anti-PD-1 antibody” refers to an antibody or antigen binding fragmentthereof that specifically binds a PD-1 polypeptide. Exemplary anti-PD-1antibodies are described for example at U.S. Pat. Nos. 7,521,051;8,008,449; 8,354,509; 9,073,994; 9,393,301; 9,402,899; and 9,439,962,which are herein incorporated by reference. Exemplary anti-PD-1antibodies include, without limitation, nivolumab, pembrolizumab,pidilizumab, and AMP-514.

“Antigen-binding domain,” “antigen-binding fragment,” and “bindingfragment” refer to a part of an antibody molecule that comprises aminoacids responsible for the specific binding between the antibody and theantigen. In instances, where an antigen is large, the antigen-bindingdomain may only bind to a part of the antigen. A portion of the antigenmolecule that is responsible for specific interactions with theantigen-binding domain is referred to as “epitope” or “antigenicdeterminant.” An antigen-binding domain typically comprises an antibodylight chain variable region (VL) and an antibody heavy chain variableregion (VH), however, it does not necessarily have to comprise both. Forexample, a so-called Fd antibody fragment consists only of a VH domain,but still retains some antigen-binding function of the intact antibody.Binding fragments of an antibody are produced by recombinant DNAtechniques, or by enzymatic or chemical cleavage of intact antibodies.Binding fragments include Fab, Fab′, F(ab′)2, Fv, and single-chainantibodies. An antibody other than a “bispecific” or “bifunctional”antibody is understood to have each of its binding sites identical.Digestion of antibodies with the enzyme, papain, results in twoidentical antigen-binding fragments, known also as “Fab” fragments, anda “Fc” fragment, having no antigen-binding activity but having theability to crystallize. Digestion of antibodies with the enzyme, pepsin,results in the a F(ab′)2 fragment in which the two arms of the antibodymolecule remain linked and comprise two-antigen binding sites. TheF(ab′)2 fragment has the ability to crosslink antigen. “Fv” when usedherein refers to the minimum fragment of an antibody that retains bothantigen-recognition and antigen-binding sites. “Fab” when used hereinrefers to a fragment of an antibody that comprises the constant domainof the light chain and the CH1 domain of the heavy chain.

“mAb” refers to monoclonal antibody. Antibodies of the presentdisclosure comprise without limitation whole native antibodies,bispecific antibodies; chimeric antibodies; Fab, Fab′, single chain Vregion fragments (scFv), fusion polypeptides, and unconventionalantibodies.

“Antisense activity” means any detectable and/or measurable activityattributable to the hybridization of an antisense compound to its targetnucleic acid. In certain embodiments, antisense activity is a decreasein the amount or expression of a target nucleic acid or protein encodedby such target nucleic acid compared to target nucleic acid levels ortarget protein levels in the absence of the antisense compound to thetarget.

“Antisense compound” means a compound comprising an oligonucleotide andoptionally one or more additional features, such as a conjugate group orterminal group. Examples of antisense compounds include single-strandedand double-stranded compounds, such as, oligonucleotides, ribozymes,siRNAs, shRNAs, ssRNAs, and occupancy-based compounds.

“Antisense inhibition” means reduction of target nucleic acid levels inthe presence of an antisense compound complementary to a target nucleicacid compared to target nucleic acid levels in the absence of theantisense compound.

“Antisense mechanisms” are all those mechanisms involving hybridizationof a compound with target nucleic acid, wherein the outcome or effect ofthe hybridization is either target degradation or target occupancy withconcomitant stalling of the cellular machinery involving, for example,transcription or splicing.

“Antisense oligonucleotide” means an oligonucleotide having a nucleobasesequence that is complementary to a target nucleic acid or region orsegment thereof. In certain embodiments, an antisense oligonucleotide isspecifically hybridizable to a target nucleic acid or region or segmentthereof.

“Bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclicsugar moiety. “Bicyclic sugar” or “bicyclic sugar moiety” means amodified sugar moiety comprising two rings, wherein the second ring isformed via a bridge connecting two of the atoms in the first ringthereby forming a bicyclic structure. In certain embodiments, the firstring of the bicyclic sugar moiety is a furanosyl moiety. In certainembodiments, the bicyclic sugar moiety does not comprise a furanosylmoiety.

“Branching group” means a group of atoms having at least 3 positionsthat are capable of forming covalent linkages to at least 3 groups. Incertain embodiments, a branching group provides a plurality of reactivesites for connecting tethered ligands to an oligonucleotide via aconjugate linker and/or a cleavable moiety.

“Cell-targeting moiety” means a conjugate group or portion of aconjugate group that is capable of binding to a particular cell type orparticular cell types.

“cEt” or “constrained ethyl” means a bicyclic furanosyl sugar moietycomprising a bridge connecting the 4′-carbon and the 2′-carbon, whereinthe bridge has the formula: 4′-CH(CH₃)—O-2′.

“cEt nucleoside” means a nucleoside comprising a cEt modified sugarmoiety.

“Chemical modification” in a compound describes the substitutions orchanges through chemical reaction, of any of the units in the compoundrelative to the original state of such unit. “Modified nucleoside” meansa nucleoside having, independently, a modified sugar moiety and/ormodified nucleobase. “Modified oligonucleotide” means an oligonucleotidecomprising at least one modified internucleoside linkage, a modifiedsugar, and/or a modified nucleobase.

“Chemically distinct region” refers to a region of a compound that is insome way chemically different than another region of the same compound.For example, a region having 2′-O-methoxyethyl nucleotides is chemicallydistinct from a region having nucleotides without 2′-O-methoxyethylmodifications.

“Chimeric antisense compounds” means antisense compounds that have atleast 2 chemically distinct regions, each position having a plurality ofsubunits.

“Chirally enriched population” means a plurality of molecules ofidentical molecular formula, wherein the number or percentage ofmolecules within the population that contain a particular stereochemicalconfiguration at a particular chiral center is greater than the numberor percentage of molecules expected to contain the same particularstereochemical configuration at the same particular chiral center withinthe population if the particular chiral center were stereorandom.Chirally enriched populations of molecules having multiple chiralcenters within each molecule may contain one or more sterorandom chiralcenters. In certain embodiments, the molecules are modifiedoligonucleotides. In certain embodiments, the molecules are compoundscomprising modified oligonucleotides.

“Cleavable bond” means any chemical bond capable of being split. Incertain embodiments, a cleavable bond is selected from among: an amide,a polyamide, an ester, an ether, one or both esters of a phosphodiester,a phosphate ester, a carbamate, a di-sulfide, or a peptide.

“Cleavable moiety” means a bond or group of atoms that is cleaved underphysiological conditions, for example, inside a cell, an animal, or ahuman.

“Complementary” in reference to an oligonucleotide means the nucleobasesequence of such oligonucleotide or one or more regions thereof matchesthe nucleobase sequence of another oligonucleotide or nucleic acid orone or more regions thereof when the two nucleobase sequences arealigned in opposing directions. Nucleobase matches or complementarynucleobases, as described herein, are limited to the following pairs:adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C)and guanine (G), and 5-methyl cytosine (mC) and guanine (G) unlessotherwise specified. Complementary oligonucleotides and/or nucleic acidsneed not have nucleobase complementarity at each nucleoside and mayinclude one or more nucleobase mismatches. By contrast, “fullycomplementary” or “100% complementary” in reference to oligonucleotidesmeans that such oligonucleotides have nucleobase matches at eachnucleoside without any nucleobase mismatches.

“Conjugate group” means a group of atoms that is attached to anoligonucleotide. Conjugate groups include a conjugate moiety and aconjugate linker that attaches the conjugate moiety to theoligonucleotide.

“Conjugate linker” means a group of atoms comprising at least one bondthat connects a conjugate moiety to an oligonucleotide.

“Conjugate moiety” means a group of atoms that is attached to anoligonucleotide via a conjugate linker.

“Contiguous” in the context of an oligonucleotide refers to nucleosides,nucleobases, sugar moieties, or internucleoside linkages that areimmediately adjacent to each other. For example, “contiguousnucleobases” means nucleobases that are immediately adjacent to eachother in a sequence.

“Designing” or “Designed to” refer to the process of designing acompound that specifically hybridizes with a selected nucleic acidmolecule.

“Diluent” means an ingredient in a composition that lackspharmacological activity, but is pharmaceutically necessary ordesirable. For example, the diluent in an injected composition can be aliquid, e.g. saline solution.

“Differently modified” means chemical modifications or chemicalsubstituents that are different from one another, including absence ofmodifications. Thus, for example, a MOE nucleoside and an unmodified DNAnucleoside are “differently modified,” even though the DNA nucleoside isunmodified. Likewise, DNA and RNA are “differently modified,” eventhough both are naturally-occurring unmodified nucleosides. Nucleosidesthat are the same but for comprising different nucleobases are notdifferently modified. For example, a nucleoside comprising a 2′-OMemodified sugar and an unmodified adenine nucleobase and a nucleosidecomprising a 2′-OMe modified sugar and an unmodified thymine nucleobaseare not differently modified.

“Dose” means a specified quantity of a compound or pharmaceutical agentprovided in a single administration, or in a specified time period. Incertain embodiments, a dose may be administered in two or more boluses,tablets, or injections. For example, in certain embodiments, wheresubcutaneous administration is desired, the desired dose may require avolume not easily accommodated by a single injection. In suchembodiments, two or more injections may be used to achieve the desireddose. In certain embodiments, a dose may be administered in two or moreinjections to minimize injection site reaction in an individual. Inother embodiments, the compound or pharmaceutical agent is administeredby infusion over an extended period of time or continuously. Doses maybe stated as the amount of pharmaceutical agent per hour, day, week ormonth.

“Dosing regimen” is a combination of doses designed to achieve one ormore desired effects.

“Double-stranded antisense compound” means an antisense compoundcomprising two oligomeric compounds that are complementary to each otherand form a duplex, and wherein one of the two said oligomeric compoundscomprises an oligonucleotide.

“Effective amount” means the amount of compound sufficient to effectuatea desired physiological outcome in an individual in need of thecompound. The effective amount may vary among individuals depending onthe health and physical condition of the individual to be treated, thetaxonomic group of the individuals to be treated, the formulation of thecomposition, assessment of the individual's medical condition, and otherrelevant factors.

“Efficacy” means the ability to produce a desired effect.

“Expression” includes all the functions by which a gene's codedinformation is converted into structures present and operating in acell. Such structures include, but are not limited to, the products oftranscription and translation.

“Gapmer” means an oligonucleotide comprising an internal region having aplurality of nucleosides that support RNase H cleavage positionedbetween external regions having one or more nucleosides, wherein thenucleosides comprising the internal region are chemically distinct fromthe nucleoside or nucleosides comprising the external regions. Theinternal region may be referred to as the “gap” and the external regionsmay be referred to as the “wings.”

“Hybridization” means the annealing of oligonucleotides and/or nucleicacids. While not limited to a particular mechanism, the most commonmechanism of hybridization involves hydrogen bonding, which may beWatson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, betweencomplementary nucleobases. In certain embodiments, complementary nucleicacid molecules include, but are not limited to, an antisense compoundand a nucleic acid target. In certain embodiments, complementary nucleicacid molecules include, but are not limited to, an oligonucleotide and anucleic acid target.

“Immediately adjacent” means there are no intervening elements betweenthe immediately adjacent elements of the same kind (e.g. no interveningnucleobases between the immediately adjacent nucleobases).

“Individual” means a human or non-human animal selected for treatment ortherapy.

“Inhibiting the expression or activity” refers to a reduction orblockade of the expression or activity relative to the expression ofactivity in an untreated or control sample and does not necessarilyindicate a total elimination of expression or activity.

“Internucleoside linkage” means a group or bond that forms a covalentlinkage between adjacent nucleosides in an oligonucleotide. “Modifiedinternucleoside linkage” means any internucleoside linkage other than anaturally occurring, phosphate internucleoside linkage. Non-phosphatelinkages are referred to herein as modified internucleoside linkages.

“Lengthened oligonucleotides” are those that have one or more additionalnucleosides relative to an oligonucleotide disclosed herein, e.g. aparent oligonucleotide.

“Linked nucleosides” means adjacent nucleosides linked together by aninternucleoside linkage.

“Linker-nucleoside” means a nucleoside that links an oligonucleotide toa conjugate moiety. Linker-nucleosides are located within the conjugatelinker of a compound. Linker-nucleosides are not considered part of theoligonucleotide portion of a compound even if they are contiguous withthe oligonucleotide.

“Mismatch” or “non-complementary” means a nucleobase of a firstoligonucleotide that is not complementary to the correspondingnucleobase of a second oligonucleotide or target nucleic acid when thefirst and second oligonucleotides are aligned. For example, nucleobasesincluding but not limited to a universal nucleobase, inosine, andhypoxanthine, are capable of hybridizing with at least one nucleobasebut are still mismatched or non-complementary with respect to nucleobaseto which it hybridized. As another example, a nucleobase of a firstoligonucleotide that is not capable of hybridizing to the correspondingnucleobase of a second oligonucleotide or target nucleic acid when thefirst and second oligonucleotides are aligned is a mismatch ornon-complementary nucleobase.

“Modulating” refers to changing or adjusting a feature in a cell,tissue, organ or organism. For example, modulating YAP1 RNA can mean toincrease or decrease the level of YAP1 RNA and/or YAP1 protein in acell, tissue, organ or organism. A “modulator” effects the change in thecell, tissue, organ or organism. For example, a YAP1 compound can be amodulator that decreases the amount of YAP1 RNA and/or YAP1 protein in acell, tissue, organ or organism.

“MOE” means methoxyethyl.

“Monomer” refers to a single unit of an oligomer. Monomers include, butare not limited to, nucleosides and nucleotides.

“Motif” means the pattern of unmodified and/or modified sugar moieties,nucleobases, and/or internucleoside linkages, in an oligonucleotide.

“Natural” or “naturally occurring” means found in nature.

“Non-bicyclic modified sugar” or “non-bicyclic modified sugar moiety”means a modified sugar moiety that comprises a modification, such as asubstituent, that does not form a bridge between two atoms of the sugarto form a second ring.

“Nucleic acid” refers to molecules composed of monomeric nucleotides. Anucleic acid includes, but is not limited to, ribonucleic acids (RNA),deoxyribonucleic acids (DNA), single-stranded nucleic acids, anddouble-stranded nucleic acids.

“Nucleobase” means a heterocyclic moiety capable of pairing with a baseof another nucleic acid. As used herein a “naturally occurringnucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), andguanine (G). A “modified nucleobase” is a naturally occurring nucleobasethat is chemically modified. A “universal base” or “universalnucleobase” is a nucleobase other than a naturally occurring nucleobaseand modified nucleobase, and is capable of pairing with any nucleobase.

“Nucleobase sequence” means the order of contiguous nucleobases in anucleic acid or oligonucleotide independent of any sugar orinternucleoside linkage.

“Nucleoside” means a compound comprising a nucleobase and a sugarmoiety. The nucleobase and sugar moiety are each, independently,unmodified or modified. “Modified nucleoside” means a nucleosidecomprising a modified nucleobase and/or a modified sugar moiety.Modified nucleosides include abasic nucleosides, which lack anucleobase.

“Oligomeric compound” means a compound comprising a singleoligonucleotide and optionally one or more additional features, such asa conjugate group or terminal group.

“Oligonucleotide” means a polymer of linked nucleosides each of whichcan be modified or unmodified, independent one from another. Unlessotherwise indicated, oligonucleotides consist of 8-80 linkednucleosides. “Modified oligonucleotide” means an oligonucleotide,wherein at least one sugar, nucleobase, or internucleoside linkage ismodified. “Unmodified oligonucleotide” means an oligonucleotide thatdoes not comprise any sugar, nucleobase, or internucleosidemodification.

“Parent oligonucleotide” means an oligonucleotide whose sequence is usedas the basis of design for more oligonucleotides of similar sequence butwith different lengths, motifs, and/or chemistries. The newly designedoligonucleotides may have the same or overlapping sequence as the parentoligonucleotide.

“Parenteral administration” means administration through injection orinfusion. Parenteral administration includes subcutaneousadministration, intravenous administration, intramuscularadministration, intraarterial administration, intraperitonealadministration, or intracranial administration, e.g. intrathecal orintracerebroventricular administration.

“Pharmaceutically acceptable carrier or diluent” means any substancesuitable for use in administering to an individual. For example, apharmaceutically acceptable carrier can be a sterile aqueous solution,such as PBS or water-for-injection.

“Pharmaceutically acceptable salts” means physiologically andpharmaceutically acceptable salts of compounds, such as oligomericcompounds or oligonucleotides, i.e., salts that retain the desiredbiological activity of the parent compound and do not impart undesiredtoxicological effects thereto.

“Pharmaceutical agent” means a compound that provides a therapeuticbenefit when administered to an individual.

“Pharmaceutical composition” means a mixture of substances suitable foradministering to an individual. For example, a pharmaceuticalcomposition may comprise one or more compounds or salt thereof and asterile aqueous solution.

“Phosphorothioate linkage” means a modified phosphate linkage in whichone of the non-bridging oxygen atoms is replaced with a sulfur atom. Aphosphorothioate internucleoside linkage is a modified internucleosidelinkage.

“Phosphorus moiety” means a group of atoms comprising a phosphorus atom.In certain embodiments, a phosphorus moiety comprises a mono-, di-, ortri-phosphate, or phosphorothioate.

“Portion” means a defined number of contiguous (i.e., linked)nucleobases of a nucleic acid. In certain embodiments, a portion is adefined number of contiguous nucleobases of a target nucleic acid. Incertain embodiments, a portion is a defined number of contiguousnucleobases of an oligomeric compound.

“Prevent” refers to delaying or forestalling the onset, development orprogression of a disease, disorder, or condition for a period of timefrom minutes to indefinitely.

“Prodrug” means a compound in a form outside the body which, whenadministered to an individual, is metabolized to another form within thebody or cells thereof. In certain embodiments, the metabolized form isthe active, or more active, form of the compound (e.g., drug). Typicallyconversion of a prodrug within the body is facilitated by the action ofan enzyme(s) (e.g., endogenous or viral enzyme) or chemical(s) presentin cells or tissues, and/or by physiologic conditions.

“Reduce” means to bring down to a smaller extent, size, amount, ornumber.

“RefSeq No.” is a unique combination of letters and numbers assigned toa sequence to indicate the sequence is for a particular targettranscript (e.g., target gene). Such sequence and information about thetarget gene (collectively, the gene record) can be found in a geneticsequence database. Genetic sequence databases include the NCBI ReferenceSequence database, GenBank, the European Nucleotide Archive, and the DNAData Bank of Japan (the latter three forming the InternationalNucleotide Sequence Database Collaboration or INSDC).

“Region” is defined as a portion of the target nucleic acid having atleast one identifiable structure, function, or characteristic.

“RNAi compound” means an antisense compound that acts, at least in part,through RISC or Ago2, but not through RNase H, to modulate a targetnucleic acid and/or protein encoded by a target nucleic acid. RNAicompounds include, but are not limited to double-stranded siRNA,single-stranded RNA (ssRNA), and microRNA, including microRNA mimics.

“Segments” are defined as smaller or sub-portions of regions within anucleic acid.

“Side effects” means physiological disease and/or conditionsattributable to a treatment other than the desired effects. In certainembodiments, side effects include injection site reactions, liverfunction test abnormalities, renal function abnormalities, livertoxicity, renal toxicity, central nervous system abnormalities,myopathies, and malaise. For example, increased aminotransferase levelsin serum may indicate liver toxicity or liver function abnormality. Forexample, increased bilirubin may indicate liver toxicity or liverfunction abnormality.

“Single-stranded” in reference to a compound means the compound has onlyone oligonucleotide. “Self-complementary” means an oligonucleotide thatat least partially hybridizes to itself. A compound consisting of oneoligonucleotide, wherein the oligonucleotide of the compound isself-complementary, is a single-stranded compound. A single-strandedcompound may be capable of binding to a complementary compound to form aduplex.

“Sites” are defined as unique nucleobase positions within a targetnucleic acid.

“Specifically hybridizable” refers to an oligonucleotide having asufficient degree of complementarity between the oligonucleotide and atarget nucleic acid to induce a desired effect, while exhibiting minimalor no effects on non-target nucleic acids. In certain embodiments,specific hybridization occurs under physiological conditions.

“Specifically inhibit” with reference to a target nucleic acid means toreduce or block expression of the target nucleic acid while exhibitingfewer, minimal, or no effects on non-target nucleic acids. Reductiondoes not necessarily indicate a total elimination of the target nucleicacid's expression.

“Standard cell assay” means assay(s) described in the Examples andreasonable variations thereof

“Standard in vivo experiment” means the procedure(s) described in theExample(s) and reasonable variations thereof.

“Stereorandom chiral center” in the context of a population of moleculesof identical molecular formula means a chiral center having a randomstereochemical configuration. For example, in a population of moleculescomprising a stereorandom chiral center, the number of molecules havingthe (S) configuration of the stereorandom chiral center may be but isnot necessarily the same as the number of molecules having the (R)configuration of the stereorandom chiral center. The stereochemicalconfiguration of a chiral center is considered random when it is theresult of a synthetic method that is not designed to control thestereochemical configuration. In certain embodiments, a stereorandomchiral center is a stereorandom phosphorothioate internucleosidelinkage.

“Sugar moiety” means an unmodified sugar moiety or a modified sugarmoiety. “Unmodified sugar moiety” or “unmodified sugar” means a 2′-OH(H)furanosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), ora 2′-H(H) moiety, as found in DNA (an “unmodified DNA sugar moiety”).Unmodified sugar moieties have one hydrogen at each of the 1′, 3′, and4′ positions, an oxygen at the 3′ position, and two hydrogens at the 5′position. “Modified sugar moiety” or “modified sugar” means a modifiedfuranosyl sugar moiety or a sugar surrogate. “Modified furanosyl sugarmoiety” means a furanosyl sugar comprising a non-hydrogen substituent inplace of at least one hydrogen of an unmodified sugar moiety. In certainembodiments, a modified furanosyl sugar moiety is a 2′-substituted sugarmoiety. Such modified furanosyl sugar moieties include bicyclic sugarsand non-bicyclic sugars.

“Sugar surrogate” means a modified sugar moiety having other than afuranosyl moiety that can link a nucleobase to another group, such as aninternucleoside linkage, conjugate group, or terminal group in anoligonucleotide. Modified nucleosides comprising sugar surrogates can beincorporated into one or more positions within an oligonucleotide andsuch oligonucleotides are capable of hybridizing to complementarycompounds or nucleic acids.

“Synergy” or “synergize” refers to an effect of a combination that isgreater than additive of the effects of each component alone at the samedoses.

“YAP1” means any nucleic acid or protein of YAP1. “YAP1 nucleic acid”means any nucleic acid encoding YAP1. For example, in certainembodiments, a YAP1 nucleic acid includes a DNA sequence encoding YAP1,an RNA sequence transcribed from DNA encoding YAP1 (including genomicDNA comprising introns and exons), and an mRNA sequence encoding YAP1.“YAP1 mRNA” means an mRNA encoding a YAP1 protein. The target may bereferred to in either upper or lower case.

“YAP1 specific inhibitor” refers to any agent capable of specificallyinhibiting YAP1 RNA and/or YAP1 protein expression or activity at themolecular level. For example, YAP1 specific inhibitors include nucleicacids (including antisense compounds), peptides, antibodies, smallmolecules, and other agents capable of inhibiting the expression of YAP1RNA and/or YAP1 protein.

“Target gene” refers to a gene encoding a target.

“Targeting” means the specific hybridization of a compound to a targetnucleic acid in order to induce a desired effect.

“Target nucleic acid,” “target RNA,” “target RNA transcript” and“nucleic acid target” all mean a nucleic acid capable of being targetedby compounds described herein.

“Target region” means a portion of a target nucleic acid to which one ormore compounds is targeted.

“Target segment” means the sequence of nucleotides of a target nucleicacid to which a compound is targeted. “5′ target site” refers to the5′-most nucleotide of a target segment. “3′ target site” refers to the3′-most nucleotide of a target segment.

“Terminal group” means a chemical group or group of atoms that iscovalently linked to a terminus of an oligonucleotide.

“Therapeutically effective amount” means an amount of a compound,pharmaceutical agent, or composition that provides a therapeutic benefitto an individual.

“Treat” refers to administering a compound or pharmaceutical compositionto an animal in order to effect an alteration or improvement of adisease, disorder, or condition in the animal.

Certain Embodiments

Certain embodiments provide methods, compounds and compositions forinhibiting YAP1 expression.

Certain embodiments provide compounds targeted to a YAP1 nucleic acid.In certain embodiments, the YAP1 nucleic acid has the sequence set forthin RefSeq or GENBANK Accession No. NM_001282101.1 (SEQ ID NO: 1) orNC_000011.10 truncated from nucleotides 102107001 to 102236000 (SEQ IDNO: 2), each of which is incorporated by reference in its entirety. Incertain embodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 23-2940. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 10 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 9 to 80 linked nucleosides and having anucleobase sequence comprising at least 9 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 23-2940. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 10 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 10 to 80 linked nucleosides and having anucleobase sequence comprising at least 10 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 23-2940. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 10 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 11 to 80 linked nucleosides and having anucleobase sequence comprising at least 11 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 23-2940. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 11 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 12 to 80 linked nucleosides and having anucleobase sequence comprising at least 12 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 23-2940. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 12 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 23-2940. In certain embodiments, the compound is an antisensecompound or oligomeric compound. In certain embodiments, the compound issingle-stranded. In certain embodiments, the compound isdouble-stranded. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides wherein the nucleobase sequenceof the modified oligonucleotide comprises an at least 8, 9, 10, 11, 12,13, 14, 15, or 16 contiguous nucleobase portion complementary to anequal length portion within nucleotides 2565-2580, 2566-2581, or4600-4615 of SEQ ID NO: 1. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 to 30 linkednucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides wherein the nucleobase sequenceof the modified oligonucleotide comprises an at least 8, 9, 10, 11, 12,13, 14, 15, or 16 contiguous nucleobase portion complementary to anequal length portion within nucleotides 123590-123605, 117330-117345,117761-117776, 117757-117772, 117758-117773, 117330-117345,119672-119687, 123591-123606, 125625-125640, or 117755-117770 of SEQ IDNO: 2. In certain embodiments, the modified oligonucleotide consists of10 to 30 linked nucleosides. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides wherein the nucleobase sequenceof the modified oligonucleotide is complementary within nucleotides2565-2580, 2566-2581, or 4600-4615 of SEQ ID NO: 1. In certainembodiments, the modified oligonucleotide consists of 10 to 30 linkednucleosides. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides wherein the nucleobase sequenceof the modified oligonucleotide is complementary within nucleotides123590-123605, 117330-117345, 117761-117776, 117757-117772,117758-117773, 117330-117345, 119672-119687, 123591-123606,125625-125640, or 117755-117770 of SEQ ID NO: 2. In certain embodiments,the modified oligonucleotide consists of 10 to 30 linked nucleosides. Incertain embodiments, the modified oligonucleotide consists of 16 to 30linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides wherein the nucleobase sequenceof the modified oligonucleotide comprises an at least 8, 9, 10, 11, 12,13, 14, 15, or 16 contiguous nucleobase portion of any one of thenucleobase sequences of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404,1101, 2812, 1200, or 2863. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 to 30 linkednucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certainembodiments, the modified oligonucleotide consists of 16 to 30 linkednucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 linked nucleosides and having a nucleobase sequenceconsisting of the nucleobase sequence of any one of SEQ ID NOs: 810,1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

In certain embodiments, a compound targeted to YAP1 is ION 1198440. Outof over 3,000 compounds that were screened as described in the Examplessection below, ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605,1198623, 1198728, 1198831, or 1198872 emerged as the top lead compounds.In particular, ION 1198440 exhibited the best combination of propertiesin terms of potency and tolerability out of over 3,000 compounds.

In certain embodiments, any of the foregoing modified oligonucleotideshas at least one modified internucleoside linkage, at least one modifiedsugar, and/or at least one modified nucleobase.

In certain embodiments, at least one nucleoside of any of the foregoingmodified oligonucleotides comprises a modified sugar. In certainembodiments, the modified sugar comprises a 2′-O-methoxyethyl group. Incertain embodiments, the modified sugar is a bicyclic sugar, such as a4′-CH(CH₃)—O-2′ group, a 4′-CH₂—O-2′ group, or a 4′-(CH₂)₂—O-2′group.

In certain embodiments, at least one internucleoside linkage of themodified oligonucleotide is a modified internucleoside linkage, such asa phosphorothioate internucleoside linkage.

In certain embodiments, at least one nucleobase of the foregoingmodified oligonucleotides is a modified nucleobase, such as5-methylcytosine.

In certain embodiments, any of the foregoing modified oligonucleotideshas:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 80 linked nucleosides and has anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200,or 2863.

In certain embodiments, the modified oligonucleotide consists of 16 to30 linked nucleosides and has a nucleobase sequence comprising thenucleobase sequence recited in any one of SEQ ID NOs: 810, 1404, 2868,2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, themodified oligonucleotide consists of 16 linked nucleosides and has anucleobase sequence consisting of the nucleobase sequence recited in anyone of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200,or 2863.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 23-2940, wherein the modified oligonucleotide has:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200,or 2863, wherein the modified oligonucleotide has:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 810 and 1404, wherein the modified oligonucleotidehas:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein each internucleoside linkage is aphosphorothioate linkage; and wherein each cytosine is a5-methylcytosine. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in SEQ IDNO: 2868, wherein the modified oligonucleotide has a gapmer consistingof a 5′-region, a 3′-region, and a central region positioned between the5′-region and the 3′-region wherein:

the 5′-region consists of 3 linked modified nucleosides, wherein eachnucleoside of the 5′-region comprises a cEt nucleoside;

the 3′-region consists of 3 linked modified nucleosides, wherein eachnucleoside of the 3′-region comprises a cEt nucleoside;

the central region consists of 10 linked nucleosides, wherein the secondnucleoside from the 5′ end of the central region comprises a 2′-O-methylmodified sugar moiety and the first and third through tenth nucleosidesfrom the 5′ end of the central region each comprises a2′deoxynucleoside;

wherein each internucleoside linkage is a phosphorothioate linkage; and

wherein each cytosine is a 5-methylcytosine. In certain embodiments, themodified oligonucleotide consists of 16 to 30 linked nucleosides. Incertain embodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide having a nucleobase sequence comprising the nucleobasesequence recited in SEQ ID NO: 2868; wherein the modifiedoligonucleotide comprises the sugar motif kkk-d-y-d(8)-kkk, wherein “k”indicates a cEt modified sugar moiety, “d” indicates an unmodified2′-deoxyribosyl sugar moiety, and “y” indicates a 2′-O-methyl modifiedsugar moiety; wherein each internucleoside linkage is a phosphorothioatelinkage; and wherein each cytosine is a 5-methylcytosine. In certainembodiments, the modified oligonucleotide consists of 16 to 30 linkednucleosides. In certain embodiments, the modified oligonucleotideconsists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of ION 1197270having the nucleobase sequence and chemical motif:TksTksAksAdsAysGdsTdsGdsTdsAdsTdsGdsTdsmCksAksGk, wherein “d” representsa 2′-deoxyribose sugar, “k” represents a cEt modified sugar, “y”represents a 2′-O-methyl sugar, “s” represents a phosphorothioateinternucleoside linkage, and “mC” refers to a 5-methylcytosine. Incertain embodiments, the modified oligonucleotide consists of 16 to 30linked nucleosides. In certain embodiments, the modified oligonucleotideconsists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in SEQ IDNO: 2864, wherein the modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein the 5′ wing segment comprises a cEtnucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethylnucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein eachinternucleoside linkage is a phosphorothioate linkage; and wherein eachcytosine is a 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in SEQ IDNOs: 1404 or 1101, wherein the modified oligonucleotide has:

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of the 5′ wing segmentcomprises a cEt nucleoside; wherein the 3′ wing segment comprises a cEtnucleoside, a cEt nucleoside, a cEt nucleoside, and a 2′-O-methoxyethylnucleoside in the 5′ to 3′ direction; wherein each internucleosidelinkage is a phosphorothioate linkage; and wherein each cytosine is a5-methylcytosine. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in SEQ IDNO: 2812, wherein the modified oligonucleotide has:

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein the 5′ wing segment comprises a cEtnucleoside, a 2′-O-methoxyethyl nucleoside, and a cEt nucleoside in the5′ to 3′ direction; wherein the 3′ wing segment comprises a2′-O-methoxyethyl nucleoside, a 2′-O-methoxyethyl nucleoside, a cEtnucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein eachinternucleoside linkage is a phosphorothioate linkage; and wherein eachcytosine is a 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in SEQ IDNOs: 1200 or 2863, wherein the modified oligonucleotide has:

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of the 5′ wing segmentcomprises a cEt nucleoside; wherein the 3′ wing segment comprises a cEtnucleoside, a 2′-O-methoxyethyl nucleoside, a cEt nucleoside, a2′-O-methoxyethyl nucleoside, and a cEt nucleoside in the 5′ to 3′direction; wherein each internucleoside linkage is a phosphorothioatelinkage; and wherein each cytosine is a 5-methylcytosine. In certainembodiments, the modified oligonucleotide consists of 16 to 30 linkednucleosides. In certain embodiments, the modified oligonucleotideconsists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in SEQ IDNO: 2865, wherein the modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein the 5′ wing segment comprises a cEtnucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethylnucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein eachinternucleoside linkage is a phosphorothioate linkage; and wherein eachcytosine is a 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

Certain embodiments provide a modified oligonucleotide, wherein theanion form of the modified oligonucleotide has the following chemicalstructure:

or a salt thereof.

Certain embodiments provide a modified oligonucleotide according to thefollowing chemical structure:

or a salt thereof.

Certain embodiments provide a modified oligonucleotide according to thefollowing chemical structure:

Under certain conditions, certain compounds disclosed herein act asacids. Although such compounds may be drawn or described in protonated(free acid) form, or ionized and in association with a cation (salt)form, aqueous solutions of such compounds exist in equilibrium amongsuch forms. For example, a phosphate linkage of an oligonucleotide inaqueous solution exists in equilibrium among free acid, anion and saltforms. Unless otherwise indicated, compounds described herein areintended to include all such forms. Moreover, certain oligonucleotideshave several such linkages, each of which is in equilibrium. Thus,oligonucleotides in solution exist in an ensemble of forms at multiplepositions all at equilibrium. Unless otherwise indicated, anoligonucleotide described herein and the term “oligonucleotide” areintended to include all such forms. Drawn structures necessarily depicta single form. Nevertheless, unless otherwise indicated, such drawingsare likewise intended to include corresponding forms. Herein, astructure depicting the free acid of a compound followed by the term “ora salt thereof” expressly includes all such forms that may be fully orpartially protonated/de-protonated/in association with a cation. Incertain instances, one or more specific cation is identified.

In any of the foregoing embodiments, the compound or oligonucleotide canbe at least 85%, at least 90%, at least 95%, at least 98%, at least 99%,or 100% complementary to a nucleic acid encoding YAP1.

In any of the foregoing embodiments, the compound can besingle-stranded. In certain embodiments, the compound comprisesdeoxyribonucleotides. In certain embodiments, the compound isdouble-stranded. In certain embodiments, the compound is double-strandedand comprises ribonucleotides. In any of the foregoing embodiments, thecompound can be an antisense compound or oligomeric compound.

In any of the foregoing embodiments, the compound can consist of 8 to80, 10 to 30, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linkednucleosides. In certain embodiments, the compound comprises or consistsof an oligonucleotide.

In certain embodiments, compounds or compositions provided hereincomprise a salt of the modified oligonucleotide. In certain embodiments,the salt is a sodium salt. In certain embodiments, the salt is apotassium salt.

In certain embodiments, the compounds or compositions as describedherein are highly tolerable as demonstrated by having at least one of anincrease an alanine transaminase (ALT) or aspartate transaminase (AST)value of no more than 4 fold, 3 fold, or 2 fold over saline treatedanimals or an increase in liver, spleen, or kidney weight of no morethan 30%, 20%, 15%, 12%, 10%, 5%, or 2% compared to control treatedanimals. In certain embodiments, the compounds or compositions asdescribed herein are highly tolerable as demonstrated by having noincrease of ALT or AST over control treated animals. In certainembodiments, the compounds or compositions as described herein arehighly tolerable as demonstrated by having no increase in liver, spleen,or kidney weight over control animals.

Certain embodiments provide a composition comprising the compound of anyof the aforementioned embodiments or salt thereof and at least one of apharmaceutically acceptable carrier or diluent. In certain embodiments,the composition has a viscosity less than about 40 centipoise (cP), lessthan about 30 centipose (cP), less than about 20 centipose (cP), lessthan about 15 centipose (cP), or less than about 10 centipose (cP). Incertain embodiments, the composition having any of the aforementionedviscosities comprises a compound provided herein at a concentration ofabout 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL,about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275 mg/mL, orabout 300 mg/mL. In certain embodiments, the composition having any ofthe aforementioned viscosities and/or compound concentrations has atemperature of room temperature or about 20° C., about 21° C., about 22°C., about 23° C., about 24° C., about 25° C., about 26° C., about 27°C., about 28° C., about 29° C., or about 30° C.

Non-limiting numbered embodiments include:

E1. A compound comprising a modified oligonucleotide consisting of 8 to80 linked nucleosides having a nucleobase sequence comprising at least 8contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:23-2940.

E2. A compound comprising a modified oligonucleotide 9 to 80 linkednucleosides in length having a nucleobase sequence comprising at least 9contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:23-2940.

E3. A compound comprising a modified oligonucleotide 10 to 80 linkednucleosides in length having a nucleobase sequence comprising at least10 contiguous nucleobases of any of the nucleobase sequences of SEQ IDNOs: 23-2940.

E4. A compound comprising a modified oligonucleotide 11 to 80 linkednucleosides in length having a nucleobase sequence comprising at least11 contiguous nucleobases of any of the nucleobase sequences of SEQ IDNOs: 23-2940.

E5. A compound comprising a modified oligonucleotide 12 to 80 linkednucleosides in length having a nucleobase sequence comprising at least12 contiguous nucleobases of any of the nucleobase sequences of SEQ IDNOs: 23-2940.

E6. A compound comprising a modified oligonucleotide consisting of 16 to80 linked nucleosides having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 23-2940.

E7. A compound comprising a modified oligonucleotide having a nucleobasesequence consisting of the nucleobase sequence of any one of SEQ ID NOs:23-2940.

E8. A compound comprising a modified oligonucleotide consisting of 8 to80 linked nucleosides complementary within nucleotides 2565-2580,2566-2581, or 4600-4615 of SEQ ID NO: 1 or within nucleotides123590-123605, 117330-117345, 117761-117776, 117757-117772,117758-117773, 117330-117345, 119672-119687, 123591-123606,125625-125640, or 117755-117770 of SEQ ID NO: 2.

E9. A compound comprising a modified oligonucleotide consisting of 8 to80 linked nucleosides having a nucleobase sequence comprising at least 8contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E10. A compound comprising a modified oligonucleotide 9 to 80 linkednucleosides in length having a nucleobase sequence comprising at least 9contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E11. A compound comprising a modified oligonucleotide 10 to 80 linkednucleosides in length having a nucleobase sequence comprising at least10 contiguous nucleobases of any of the nucleobase sequences of SEQ IDNOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E12. A compound comprising a modified oligonucleotide 11 to 80 linkednucleosides in length having a nucleobase sequence comprising at least11 contiguous nucleobases of any of the nucleobase sequences of SEQ IDNOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E13. A compound comprising a modified oligonucleotide 12 to 80 linkednucleosides in length having a nucleobase sequence comprising at least12 contiguous nucleobases of any of the nucleobase sequences of SEQ IDNOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E14. A compound comprising a modified oligonucleotide consisting of 8 to80 linked nucleosides having a nucleobase sequence comprising any one ofSEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or2863.

E15. A compound comprising a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or2863.

E16. A compound comprising a modified oligonucleotide consisting of 8 to80 linked nucleosides having a nucleobase sequence comprising any one ofSEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or2863.

E17. A compound comprising a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or2863.

E18. The compound of any one of embodiments E1-E17, wherein the modifiedoligonucleotide comprises at least one modified internucleoside linkage,at least one modified sugar, or at least one modified nucleobase.

E19. The compound of embodiment E18, wherein the modifiedinternucleoside linkage is a phosphorothioate internucleoside linkage.

E20. The compound of embodiment E18 or E19, wherein the modified sugaris a bicyclic sugar.

E21. The compound of embodiment E20, wherein the bicyclic sugar isselected from the group consisting of: 4′-(CH₂)—O-2′ (LNA);4′-(CH₂)₂—O-2′ (ENA); and 4′-CH(CH₃)—O-2′ (cEt).

E22. The compound of embodiment E18 or E19, wherein the modified sugaris 2′-O-methoxyethyl.

E23. The compound of any one of embodiments E18-E22, wherein themodified nucleobase is a 5-methylcytosine.

E24. The compound of any one of embodiments E1-E23, wherein the modifiedoligonucleotide comprises:

a gap segment consisting of linked 2′-deoxynucleosides;

a 5′ wing segment consisting of linked nucleosides; and

a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar.

E25. A compound comprising a modified oligonucleotide consisting of 16to 80 linked nucleosides having a nucleobase sequence comprising any oneof SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or2863, wherein the modified oligonucleotide comprises:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar.

E26. A compound comprising a modified oligonucleotide consisting of16-80 linked nucleobases having a nucleobase sequence comprising thesequence recited in any one of SEQ ID NOs: 810 and 1404, wherein themodified oligonucleotide comprises:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein each internucleoside linkage is aphosphorothioate linkage; and wherein each cytosine is a5-methylcytosine.

E27. A compound comprising a modified oligonucleotide consisting of16-80 linked nucleobases having a nucleobase sequence comprising thesequence recited in SEQ ID NOs: 2864, wherein the modifiedoligonucleotide comprises:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein the 5′ wing segment comprises a cEtnucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethylnucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein eachinternucleoside linkage is a phosphorothioate linkage; and wherein eachcytosine is a 5-methylcytosine.

E28. A compound comprising a modified oligonucleotide consisting of16-80 linked nucleobases having a nucleobase sequence comprising thesequence recited in SEQ ID NO: 2868, wherein the modifiedoligonucleotide comprises a gapmer consisting of a 5′-region, a3′-region, and a central region positioned between the 5′-region and the3′-region wherein:

-   -   the 5′-region consists of 3 linked modified nucleosides, wherein        each nucleoside of the 5′-region comprises a cEt nucleoside;

the 3′-region consists of 3 linked modified nucleosides, wherein eachnucleoside of the 3′-region comprises a cEt nucleoside;

the central region consists of 10 linked nucleosides, wherein the secondnucleoside from the 5′ end of the central region comprises a 2′-O-methylmodified sugar moiety and the first and third through tenth nucleosidesfrom the 5′ end of the central region each comprises a2′deoxynucleoside;

wherein each internucleoside linkage is a phosphorothioate linkage; and

wherein each cytosine is a 5-methylcytosine.

E29. A compound comprising a modified oligonucleotide consisting of16-80 linked nucleobases having a nucleobase sequence comprising thesequence recited in SEQ ID NOs: 1200 or 2863, wherein the modifiedoligonucleotide comprises:

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of the 5′ wing segmentcomprises a cEt nucleoside; wherein the 3′ wing segment comprises a cEtnucleoside, a 2′-O-methoxyethyl nucleoside, a cEt nucleoside, a2′-O-methoxyethyl nucleoside, and a cEt nucleoside in the 5′ to 3′direction; wherein each internucleoside linkage is a phosphorothioatelinkage; and wherein each cytosine is a 5-methylcytosine.

E30. A compound comprising or consisting of a modified oligonucleotideconsisting of 16-80 linked nucleobases having a nucleobase sequencecomprising the sequence recited in SEQ ID NO: 2865, wherein the modifiedoligonucleotide comprises:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein the 5′ wing segment comprises a cEtnucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethylnucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein eachinternucleoside linkage is a phosphorothioate linkage; and wherein eachcytosine is a 5-methylcytosine.

E31. The compound of any one of embodiments E1-E30, wherein theoligonucleotide is at least 80%, 85%, 90%, 95% or 100% complementary toany of SEQ ID NOs: 1-10.

E32. The compound of any one of embodiments E1-E31, wherein the compoundis single-stranded.

E33. The compound of any one of embodiments E1-E31, wherein the compoundis double-stranded.

E34. The compound of any one of embodiments E1-E33, wherein the compoundcomprises ribonucleotides.

E35. The compound of any one of embodiments E1-E33, wherein the compoundcomprises deoxyribonucleotides.

E36. The compound of any one of embodiments E1-E35, wherein the modifiedoligonucleotide consists of 16 to 30 linked nucleosides.

E37. The compound of any preceding embodiment E1-E36, wherein thecompound consists of the modified oligonucleotide.

E38. A compound consisting of a pharmaceutically acceptable salt of anyof the compounds of embodiments E1-E36.

E39. The compound of embodiment E38, wherein the pharmaceuticallyacceptable salt is a sodium salt.

E40. The compound of embodiment E38, wherein the pharmaceuticallyacceptable salt is a potassium salt.

E41. A compound having the formula:

or a salt thereof.

E42. A compound having the formula:

E43. A composition comprising the compound of any one of embodimentsE1-E42 and a pharmaceutically acceptable diluent or carrier.

E44. A composition comprising the compound of any one of embodimentsE1-E42 and water.

E45. A composition comprising a compound or modified oligonucleotide ofany preceding embodiment E1-E44, for use in therapy.

E46. A combination comprising the compound of any one of embodimentsE1-E42 or the composition of any of embodiments E43-E45 and a secondaryagent.

E47. The combination of embodiment E46, wherein the secondary agent is aCDK4/6 inhibitor.

E48. The combination of embodiment E47, wherein the CDK4/6 inhibitor ispalbociclib, ribociclib, or abemaciclib.

E49. The combination of embodiment E46, wherein the secondary agent isan EGFR inhibitor.

E50. The combination of embodiment E49, wherein the EGFR inhibitor iscetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib,osimertinib, gefitinib, lapatinib, or erlotinib.

E51. The combination of embodiment E46, wherein the secondary agent is akinase inhibitor.

E52. The combination of embodiment E51, wherein the kinase inhibitor issorafenib, regorafenib, or carbozantinib.

E53. A method of treating or ameliorating cancer in an individualcomprising administering to the individual a compound targeted to YAP1,thereby treating or ameliorating the cancer.

E54. The method of embodiment E53, wherein the compound is an antisensecompound targeted to YAP1.

E55. The method of embodiment E53 or E54, further comprisingadministering a secondary agent.

E56. The method of embodiment E55, wherein the secondary agent is aCDK4/6 inhibitor.

E57. The method of embodiment E56, wherein the CDK4/6 inhibitor ispalbociclib, ribociclib, or abemaciclib.

E58. The method of embodiment E55, wherein the secondary agent is anEGFR inhibitor.

E59. The method of embodiment E58, wherein the EGFR inhibitor iscetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib,osimertinib, gefitinib, lapatinib, or erlotinib.

E60. The method of embodiment E55, wherein the secondary agent is akinase inhibitor.

E61. The method of embodiment E60, wherein the kinase inhibitor issorafenib, regorafenib, or carbozantinib.

E62. The method of any of embodiments E53-E61, wherein the cancer ishepatocellular carcinoma (HCC), head and neck squamous cell carcinoma(HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamouscell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamouscell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial),esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer,tumors with mutations in SWI/SNF complex, lung cancer, non-small celllung carcinoma (NSCLC), small-cell lung carcinoma (SCLC),gastrointestinal cancer, large intestinal cancer, small intestinalcancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer,liver cancer, biliary tract cancer, urothelial cancer, breast cancer,triple-negative breast cancer (TNBC), endometrial cancer, cervicalcancer, prostate cancer, mesothelioma, chordoma, renal cancer, renalcell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skincancer, melanoma, basal cell carcinoma, merkel cell carcinoma, bloodcancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cellmalignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T celllymphoma, leukemia, or acute lymphocytic leukemia (ALL), a cancer havinga mutant FAT1 gene, a cancer having a homozygous FAT1 gene mutation, ora cancer having a heterozygous FAT1 gene mutation, a squamous cellcarcinoma (SCC) having a mutant FAT1 gene, a head and neck squamous cellcarcinoma (HNSCC) having a mutant FAT1 gene, an oral tongue squamouscell carcinoma (OTSCC) having a mutant FAT1 gene, a pharynx carcinomahaving a mutant FAT1 gene, or a laryngeal squamous cell carcinoma havinga mutant FAT1 gene.

E63. The method of any of embodiments E53-E62, wherein administering thecompound inhibits or reduces cancer cell proliferation, tumor growth, ormetastasis.

E64. A method of inhibiting expression of YAP1 in a cell comprisingcontacting the cell with a compound targeted to YAP1, thereby inhibitingexpression of YAP1 in the cell.

E65. The method of embodiment E64, wherein the cell a cancer cell.

E66. The method of embodiment E65, wherein the cancer is hepatocellularcarcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head andneck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oraltongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC),sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer,gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutationsin SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC),small-cell lung carcinoma (SCLC), gastrointestinal cancer, largeintestinal cancer, small intestinal cancer, stomach cancer, coloncancer, colorectal cancer, bladder cancer, liver cancer, biliary tractcancer, urothelial cancer, breast cancer, triple-negative breast cancer(TNBC), endometrial cancer, cervical cancer, prostate cancer,mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), braincancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cellcarcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer,myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B celllymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acutelymphocytic leukemia (ALL), a cancer having a mutant FAT1 gene, a cancerhaving a homozygous FAT1 gene mutation, or a cancer having aheterozygous FAT1 gene mutation, a squamous cell carcinoma (SCC) havinga mutant FAT1 gene, a head and neck squamous cell carcinoma (HNSCC)having a mutant FAT1 gene, an oral tongue squamous cell carcinoma(OTSCC) having a mutant FAT1 gene, a pharynx carcinoma having a mutantFAT1 gene, or a laryngeal squamous cell carcinoma having a mutant FAT1gene.

E67. A method of reducing or inhibiting cancer cell proliferation, tumorgrowth, or metastasis in an individual having cancer comprisingadministering a compound targeted to YAP1 to the individual, therebyreducing or inhibiting cancer cell proliferation, tumor growth, ormetastasis in the individual.

E68. The method of embodiment E67, wherein the individual hashepatocellular carcinoma (HCC), head and neck squamous cell carcinoma(HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamouscell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamouscell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial),esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer,tumors with mutations in SWI/SNF complex, lung cancer, non-small celllung carcinoma (NSCLC), small-cell lung carcinoma (SCLC),gastrointestinal cancer, large intestinal cancer, small intestinalcancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer,liver cancer, biliary tract cancer, urothelial cancer, breast cancer,triple-negative breast cancer (TNBC), endometrial cancer, cervicalcancer, prostate cancer, mesothelioma, chordoma, renal cancer, renalcell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skincancer, melanoma, basal cell carcinoma, merkel cell carcinoma, bloodcancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cellmalignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T celllymphoma, leukemia, or acute lymphocytic leukemia (ALL), a cancer havinga mutant FAT1 gene, a cancer having a homozygous FAT1 gene mutation, ora cancer having a heterozygous FAT1 gene mutation, a squamous cellcarcinoma (SCC) having a mutant FAT1 gene, a head and neck squamous cellcarcinoma (HNSCC) having a mutant FAT1 gene, an oral tongue squamouscell carcinoma (OTSCC) having a mutant FAT1 gene, a pharynx carcinomahaving a mutant FAT1 gene, or a laryngeal squamous cell carcinoma havinga mutant FAT1 gene.

E69. The method of any one of embodiments E64-E68, wherein the compoundis an antisense compound targeted to YAP1.

E70. The method of any one of embodiments E64-E69, wherein the compoundis the compound of any one of embodiments 1-42 or composition of any oneof embodiments 43-45.

E71. The method of any of embodiments E64-E70, wherein the compound isadministered parenterally.

E72. Use of a compound targeted to YAP1 for treating, preventing, orameliorating a cancer associated with YAP1.

E73. Use of a compound targeted to YAP1 and a secondary agent fortreating, preventing, or ameliorating a cancer associated with YAP1.

E74. The use of embodiment E73, wherein the secondary agent is a CDK4/6inhibitor.

E75. The use of embodiment E74, wherein the CDK4/6 inhibitor ispalbociclib, ribociclib, or abemaciclib.

E76. The use of embodiment E73, wherein the secondary agent is an EGFRinhibitor.

E77. The use of embodiment E76, wherein the EGFR inhibitor is cetuximab,necitumumab, panitumumab, vandetanib, dacomitinib, neratinib,osimertinib, gefitinib, lapatinib, or erlotinib.

E78. The use of embodiment E73, wherein the secondary agent is a kinaseinhibitor.

E79. The use of embodiment E78, wherein the kinase inhibitor issorafenib, regorafenib, or carbozantinib.

E80. The use of any of embodiments E72-E79, wherein the cancer ishepatocellular carcinoma (HCC), head and neck squamous cell carcinoma(HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamouscell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamouscell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial),esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer,tumors with mutations in SWI/SNF complex, lung cancer, non-small celllung carcinoma (NSCLC), small-cell lung carcinoma (SCLC),gastrointestinal cancer, large intestinal cancer, small intestinalcancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer,liver cancer, biliary tract cancer, urothelial cancer, breast cancer,triple-negative breast cancer (TNBC), endometrial cancer, cervicalcancer, prostate cancer, mesothelioma, chordoma, renal cancer, renalcell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skincancer, melanoma, basal cell carcinoma, merkel cell carcinoma, bloodcancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cellmalignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T celllymphoma, leukemia, or acute lymphocytic leukemia (ALL), a cancer havinga mutant FAT1 gene, a cancer having a homozygous FAT1 gene mutation, ora cancer having a heterozygous FAT1 gene mutation, a squamous cellcarcinoma (SCC) having a mutant FAT1 gene, a head and neck squamous cellcarcinoma (HNSCC) having a mutant FAT1 gene, an oral tongue squamouscell carcinoma (OTSCC) having a mutant FAT1 gene, a pharynx carcinomahaving a mutant FAT1 gene, or a laryngeal squamous cell carcinoma havinga mutant FAT1 gene.

E81. The use of any of embodiments E72-E80, wherein the compound is anantisense compound targeted to YAP1.

E82. The use of any of embodiments E72-E81, wherein the compound is thecompound of any one of embodiments E1-E42 or composition of any one ofembodiments E43-E45.

E83. Use of a compound targeted to YAP1 in the manufacture of amedicament for treating or ameliorating a cancer associated with YAP1.

E84. The use of embodiment E83, wherein the cancer is hepatocellularcarcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head andneck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oraltongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC),sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer,gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutationsin SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC),small-cell lung carcinoma (SCLC), gastrointestinal cancer, largeintestinal cancer, small intestinal cancer, stomach cancer, coloncancer, colorectal cancer, bladder cancer, liver cancer, biliary tractcancer, urothelial cancer, breast cancer, triple-negative breast cancer(TNBC), endometrial cancer, cervical cancer, prostate cancer,mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), braincancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cellcarcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer,myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B celllymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acutelymphocytic leukemia (ALL), a cancer having a mutant FAT1 gene, a cancerhaving a homozygous FAT1 gene mutation, or a cancer having aheterozygous FAT1 gene mutation, a squamous cell carcinoma (SCC) havinga mutant FAT1 gene, a head and neck squamous cell carcinoma (HNSCC)having a mutant FAT1 gene, an oral tongue squamous cell carcinoma(OTSCC) having a mutant FAT1 gene, a pharynx carcinoma having a mutantFAT1 gene, or a laryngeal squamous cell carcinoma having a mutant FAT1gene.

E85. The use of embodiment E83 or E84, wherein the compound is anantisense compound targeted to YAP1.

E86. The use of any one of embodiments E83-E85, wherein the compound isthe compound of any one of embodiments 1-42 or composition of any one ofembodiments E43-E45.

E87. Use of a compound targeted to YAP1 in the preparation of amedicament for treating or ameliorating a cancer associated with YAP1.

E88. The use of embodiment E87, wherein the cancer is hepatocellularcarcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head andneck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oraltongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC),sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer,gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutationsin SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC),small-cell lung carcinoma (SCLC), gastrointestinal cancer, largeintestinal cancer, small intestinal cancer, stomach cancer, coloncancer, colorectal cancer, bladder cancer, liver cancer, biliary tractcancer, urothelial cancer, breast cancer, triple-negative breast cancer(TNBC), endometrial cancer, cervical cancer, prostate cancer,mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), braincancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cellcarcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer,myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B celllymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acutelymphocytic leukemia (ALL), a cancer having a mutant FAT1 gene, a cancerhaving a homozygous FAT1 gene mutation, or a cancer having aheterozygous FAT1 gene mutation, a squamous cell carcinoma (SCC) havinga mutant FAT1 gene, a head and neck squamous cell carcinoma (HNSCC)having a mutant FAT1 gene, an oral tongue squamous cell carcinoma(OTSCC) having a mutant FAT1 gene, a pharynx carcinoma having a mutantFAT1 gene, or a laryngeal squamous cell carcinoma having a mutant FAT1gene.

E89. The use of embodiment E87 or E88, wherein the compound is anantisense compound targeted to YAP1.

E90. The use of any one of embodiments E87-E89, wherein the compound isthe compound of any one of embodiments 1-42 or composition of any one ofembodiments E43-E45.

Certain Indications

Certain embodiments provided herein relate to methods of inhibiting YAP1expression, which can be useful for treating, preventing, orameliorating a cancer associated with YAP1 in an individual, byadministration of a compound that targets YAP1. In certain embodiments,the compound can be a YAP1 specific inhibitor. In certain embodiments,the compound can be an antisense compound, oligomeric compound, oroligonucleotide targeted to YAP1.

Examples of cancers associated with YAP1 treatable, preventable, and/orameliorable with the compounds and methods provided herein includehepatocellular carcinoma (HCC), head and neck squamous cell carcinoma(HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamouscell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamouscell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial),esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer,tumors with mutations in SWI/SNF complex, lung cancer, non-small celllung carcinoma (NSCLC), small-cell lung carcinoma (SCLC),gastrointestinal cancer, large intestinal cancer, small intestinalcancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer,liver cancer, biliary tract cancer, urothelial cancer, breast cancer,triple-negative breast cancer (TNBC), endometrial cancer, cervicalcancer, prostate cancer, mesothelioma, chordoma, renal cancer, renalcell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skincancer, melanoma, basal cell carcinoma, merkel cell carcinoma, bloodcancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cellmalignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T celllymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certainembodiments, the cancer has a mutant FAT1 gene. In certain embodiments,the cancer has a homozygous or heterozygous FAT1 gene mutation. Incertain embodiments, the cancer having a mutant FAT1 gene, a homozygousFAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cellcarcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oraltongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngealsquamous cell carcinoma.

In certain embodiments, a method of treating, preventing, orameliorating a cancer associated with YAP1 in an individual comprisesadministering to the individual a compound comprising a YAP1 specificinhibitor, thereby treating, preventing, or ameliorating the cancer. Incertain embodiments, the compound comprises an antisense compoundtargeted to YAP1. In certain embodiments, the compound comprises anoligonucleotide targeted to YAP1. In certain embodiments, a compoundcomprises a modified oligonucleotide consisting of 8 to 80 linkednucleosides and having a nucleobase sequence comprising at least 8contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:23-2940. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 23-2940. In certain embodiments, a compound comprises a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404,1101, 2812, 1200, or 2863. In certain embodiments, a compound comprisesa modified oligonucleotide having a nucleobase sequence consisting ofthe nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864,2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 958499,1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831,or 1198872. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound. Incertain embodiments, the compound is administered to the individualparenterally. In certain embodiments, administering the compoundinhibits or reduces cancer cell proliferation, tumor growth, ormetastasis.

In certain embodiments, a method of treating or ameliorating canercomprises administering to the individual a compound comprising a YAP1specific inhibitor, thereby treating or ameliorating the cancer. Incertain embodiments, the cancer is hepatocellular carcinoma (HCC), headand neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynxcarcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cellcarcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g.epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer,ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNFcomplex, lung cancer, non-small cell lung carcinoma (NSCLC), small-celllung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer,small intestinal cancer, stomach cancer, colon cancer, colorectalcancer, bladder cancer, liver cancer, biliary tract cancer, urothelialcancer, breast cancer, triple-negative breast cancer (TNBC), endometrialcancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renalcancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma,glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cellcarcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma(MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma,T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). Incertain embodiments, the cancer has a mutant FAT1 gene. In certainembodiments, the cancer has a homozygous or heterozygous FAT1 genemutation. In certain embodiments, the cancer having a mutant FAT1 gene,a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation issquamous cell carcinoma (SCC), head and neck squamous cell carcinoma(HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma,or laryngeal squamous cell carcinoma. In certain embodiments, thecompound comprises an antisense compound targeted to YAP1. In certainembodiments, the compound comprises an oligonucleotide targeted to YAP1.In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:23-2940. In certain embodiments, the compound comprises a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certainembodiments, the compound comprises a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or2863. In any of the foregoing embodiments, the modified oligonucleotidecan consist of 10 to 30 linked nucleosides. In certain embodiments, thecompound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605,1198623, 1198728, 1198831, or 1198872. In any of the foregoingembodiments, the compound can be single-stranded or double-stranded. Inany of the foregoing embodiments, the compound can be an antisensecompound or oligomeric compound. In certain embodiments, the compound isadministered to the individual parenterally. In certain embodiments,administering the compound inhibits or reduces cancer cellproliferation, tumor growth, or metastasis. In certain embodiments, theindividual is identified as having or at risk of having a cancerassociated with YAP1.

In certain embodiments, a method of inhibiting expression of YAP1 in anindividual having, or at risk of having, a cancer associated with YAP1comprises administering to the individual a compound comprising a YAP1specific inhibitor, thereby inhibiting expression of YAP1 in theindividual. In certain embodiments, administering the compound inhibitsexpression of YAP1 in a cancer cell in the individual. In certainembodiments, the individual has, or is at risk of having hepatocellularcarcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head andneck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oraltongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC),sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer,gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutationsin SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC),small-cell lung carcinoma (SCLC), gastrointestinal cancer, largeintestinal cancer, small intestinal cancer, stomach cancer, coloncancer, colorectal cancer, bladder cancer, liver cancer, biliary tractcancer, urothelial cancer, breast cancer, triple-negative breast cancer(TNBC), endometrial cancer, cervical cancer, prostate cancer,mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), braincancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cellcarcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer,myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B celllymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acutelymphocytic leukemia (ALL). In certain embodiments, the cancer has amutant FAT1 gene. In certain embodiments, the cancer has a homozygous orheterozygous FAT1 gene mutation. In certain embodiments, the cancerhaving a mutant FAT1 gene, a homozygous FAT1 gene mutation, or aheterozygous FAT gene mutation is squamous cell carcinoma (SCC), headand neck squamous cell carcinoma (HNSCC), oral tongue squamous cellcarcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cellcarcinoma. In certain embodiments, the compound comprises an antisensecompound targeted to YAP1. In certain embodiments, the compoundcomprises an oligonucleotide targeted to YAP1. In certain embodiments,the compound comprises a modified oligonucleotide consisting of 8 to 80linked nucleosides and having a nucleobase sequence comprising at least8 contiguous nucleobases of any of the nucleobase sequences of SEQ IDNOs: 23-2940. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 23-2940. In certain embodiments, the compound comprises amodified oligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certainembodiments, the compound comprises a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or2863. In any of the foregoing embodiments, the modified oligonucleotidecan consist of 10 to 30 linked nucleosides. In certain embodiments, thecompound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605,1198623, 1198728, 1198831, or 1198872. In any of the foregoingembodiments, the compound can be single-stranded or double-stranded. Inany of the foregoing embodiments, the compound can be an antisensecompound or oligomeric compound. In certain embodiments, the compound isadministered to the individual parenterally. In certain embodiments,administering the compound inhibits or reduces cancer cellproliferation, tumor growth, or metastasis. In certain embodiments, theindividual is identified as having or at risk of having a cancerassociated with YAP1.

In certain embodiments, a method of inhibiting expression of YAP1 in acell comprises contacting the cell with a compound comprising a YAP1specific inhibitor, thereby inhibiting expression of YAP1 in the cell.In certain embodiments, the cell is a cancer cell. In certainembodiments, the cell is a liver cancer cell or squamous cancer cell. Incertain embodiments, the cancer cell is in the liver, head, or neck ofan individual having cancer. In certain embodiments, the cell is in anindividual who has, or is at risk of having cancer, such ashepatocellular carcinoma (HCC), head and neck squamous cell carcinoma(HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamouscell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamouscell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial),esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer,tumors with mutations in SWI/SNF complex, lung cancer, non-small celllung carcinoma (NSCLC), small-cell lung carcinoma (SCLC),gastrointestinal cancer, large intestinal cancer, small intestinalcancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer,liver cancer, biliary tract cancer, urothelial cancer, breast cancer,triple-negative breast cancer (TNBC), endometrial cancer, cervicalcancer, prostate cancer, mesothelioma, chordoma, renal cancer, renalcell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skincancer, melanoma, basal cell carcinoma, merkel cell carcinoma, bloodcancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cellmalignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T celllymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certainembodiments, the cancer has a mutant FAT1 gene. In certain embodiments,the cancer has a homozygous or heterozygous FAT1 gene mutation. Incertain embodiments, the cancer having a mutant FAT1 gene, a homozygousFAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cellcarcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oraltongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngealsquamous cell carcinoma. In certain embodiments, the compound comprisesan antisense compound targeted to YAP1. In certain embodiments, thecompound comprises an oligonucleotide targeted to YAP1. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, thecompound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 23-2940. In certain embodiments, the compound comprises amodified oligonucleotide consisting of 16 to 80 linked nucleosides andhaving a nucleobase sequence comprising the nucleobase sequence of anyone of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200,or 2863. In certain embodiments, the compound comprises a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864,2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 958499,1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831,or 1198872. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

In certain embodiments, a method of reducing or inhibiting cancer cellproliferation, tumor growth, or metastasis of an individual having, orat risk of having, a cancer associated with YAP1 comprises administeringto the individual a compound comprising a YAP1 specific inhibitor,thereby reducing or inhibiting cancer cell proliferation, tumor growth,or metastasis in the individual. In certain embodiments, the individualhas, or is at risk of having, hepatocellular carcinoma (HCC), head andneck squamous cell carcinoma (HNSCC), head and neck cancer, pharynxcarcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cellcarcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g.epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer,ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNFcomplex, lung cancer, non-small cell lung carcinoma (NSCLC), small-celllung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer,small intestinal cancer, stomach cancer, colon cancer, colorectalcancer, bladder cancer, liver cancer, biliary tract cancer, urothelialcancer, breast cancer, triple-negative breast cancer (TNBC), endometrialcancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renalcancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma,glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cellcarcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma(MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma,T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). Incertain embodiments, the cancer has a mutant FAT1 gene. In certainembodiments, the cancer has a homozygous or heterozygous FAT1 genemutation. In certain embodiments, the cancer having a mutant FAT1 gene,a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation issquamous cell carcinoma (SCC), head and neck squamous cell carcinoma(HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma,or laryngeal squamous cell carcinoma. In certain embodiments, thecompound comprises an antisense compound targeted to YAP1. In certainembodiments, the compound comprises an oligonucleotide targeted to YAP1.In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:23-2940. In certain embodiments, the compound comprises a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certainembodiments, the compound comprises a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or2863. In any of the foregoing embodiments, the modified oligonucleotidecan consist of 10 to 30 linked nucleosides. In certain embodiments, thecompound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605,1198623, 1198728, 1198831, or 1198872. In any of the foregoingembodiments, the compound can be single-stranded or double-stranded. Inany of the foregoing embodiments, the compound can be an antisensecompound or oligomeric compound. In certain embodiments, the compound isadministered to the individual parenterally. In certain embodiments, theindividual is identified as having or at risk of having a cancerassociated with YAP1.

Certain embodiments are drawn to a compound comprising a YAP1 specificinhibitor for use in treating cancer. In certain embodiments, the canceris hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma(HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamouscell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamouscell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial),esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer,tumors with mutations in SWI/SNF complex, lung cancer, non-small celllung carcinoma (NSCLC), small-cell lung carcinoma (SCLC),gastrointestinal cancer, large intestinal cancer, small intestinalcancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer,liver cancer, biliary tract cancer, urothelial cancer, breast cancer,triple-negative breast cancer (TNBC), endometrial cancer, cervicalcancer, prostate cancer, mesothelioma, chordoma, renal cancer, renalcell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skincancer, melanoma, basal cell carcinoma, merkel cell carcinoma, bloodcancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cellmalignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T celllymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certainembodiments, the cancer has a mutant FAT1 gene. In certain embodiments,the cancer has a homozygous or heterozygous FAT1 gene mutation. Incertain embodiments, the cancer having a mutant FAT1 gene, a homozygousFAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cellcarcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oraltongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngealsquamous cell carcinoma. In certain embodiments, the compound comprisesan antisense compound targeted to YAP1. In certain embodiments, thecompound comprises an oligonucleotide targeted to YAP1. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, thecompound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 23-2940. In certain embodiments, the compound comprises amodified oligonucleotide consisting of 16 to 80 linked nucleosides andhaving a nucleobase sequence comprising the nucleobase sequence of anyone of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200,or 2863. In certain embodiments, the compound comprises a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864,2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 958499,1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831,or 1198872. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to a compound comprising a YAP1 specificinhibitor for use in reducing or inhibiting cancer cell proliferation,tumor growth, or metastasis in an individual having cancer. In certainembodiments, the cancer is hepatocellular carcinoma (HCC), head and necksquamous cell carcinoma (HNSCC), head and neck cancer, pharynxcarcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cellcarcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g.epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer,ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNFcomplex, lung cancer, non-small cell lung carcinoma (NSCLC), small-celllung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer,small intestinal cancer, stomach cancer, colon cancer, colorectalcancer, bladder cancer, liver cancer, biliary tract cancer, urothelialcancer, breast cancer, triple-negative breast cancer (TNBC), endometrialcancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renalcancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma,glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cellcarcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma(MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma,T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). Incertain embodiments, the cancer has a mutant FAT1 gene. In certainembodiments, the cancer has a homozygous or heterozygous FAT1 genemutation. In certain embodiments, the cancer having a mutant FAT1 gene,a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation issquamous cell carcinoma (SCC), head and neck squamous cell carcinoma(HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma,or laryngeal squamous cell carcinoma. In certain embodiments, thecompound comprises an antisense compound targeted to YAP1. In certainembodiments, the compound comprises an oligonucleotide targeted to YAP1.In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:23-2940. In certain embodiments, the compound comprises a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certainembodiments, the compound comprises a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or2863. In any of the foregoing embodiments, the modified oligonucleotidecan consist of 10 to 30 linked nucleosides. In certain embodiments, thecompound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605,1198623, 1198728, 1198831, or 1198872. In any of the foregoingembodiments, the compound can be single-stranded or double-stranded. Inany of the foregoing embodiments, the compound can be an antisensecompound or oligomeric compound.

Certain embodiments are drawn to use of a compound comprising a YAP1specific inhibitor for the manufacture or preparation of a medicamentfor treating cancer. Certain embodiments are drawn to use of a compoundcomprising a YAP1 specific inhibitor for the preparation of a medicamentfor treating a cancer associated with YAP1. In certain embodiments, thecancer is hepatocellular carcinoma (HCC), head and neck squamous cellcarcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngealsquamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC),squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid andsynovial), esophageal cancer, gastric cancer, ovarian cancer, pancreaticcancer, tumors with mutations in SWI/SNF complex, lung cancer, non-smallcell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC),gastrointestinal cancer, large intestinal cancer, small intestinalcancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer,liver cancer, biliary tract cancer, urothelial cancer, breast cancer,triple-negative breast cancer (TNBC), endometrial cancer, cervicalcancer, prostate cancer, mesothelioma, chordoma, renal cancer, renalcell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skincancer, melanoma, basal cell carcinoma, merkel cell carcinoma, bloodcancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cellmalignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T celllymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certainembodiments, the cancer has a mutant FAT1 gene. In certain embodiments,the cancer has a homozygous or heterozygous FAT1 gene mutation. Incertain embodiments, the cancer having a mutant FAT1 gene, a homozygousFAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cellcarcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oraltongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngealsquamous cell carcinoma. In certain embodiments, the compound comprisesan antisense compound targeted to YAP1. In certain embodiments, thecompound comprises an oligonucleotide targeted to YAP1. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, thecompound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 23-2940. In certain embodiments, the compound comprises amodified oligonucleotide consisting of 16 to 80 linked nucleosides andhaving a nucleobase sequence comprising the nucleobase sequence of anyone of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200,or 2863. In certain embodiments, the compound comprises a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864,2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 958499,1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831,or 1198872. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to use of a compound comprising a YAP1specific inhibitor for the manufacture or preparation of a medicamentfor reducing or inhibiting cancer cell proliferation, tumor growth, ormetastasis in an individual having cancer. In certain embodiments, thecancer is hepatocellular carcinoma (HCC), head and neck squamous cellcarcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngealsquamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC),squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid andsynovial), esophageal cancer, gastric cancer, ovarian cancer, pancreaticcancer, tumors with mutations in SWI/SNF complex, lung cancer, non-smallcell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC),gastrointestinal cancer, large intestinal cancer, small intestinalcancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer,liver cancer, biliary tract cancer, urothelial cancer, breast cancer,triple-negative breast cancer (TNBC), endometrial cancer, cervicalcancer, prostate cancer, mesothelioma, chordoma, renal cancer, renalcell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skincancer, melanoma, basal cell carcinoma, merkel cell carcinoma, bloodcancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cellmalignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T celllymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certainembodiments, the cancer has a mutant FAT1 gene. In certain embodiments,the cancer has a homozygous or heterozygous FAT1 gene mutation. Incertain embodiments, the cancer having a mutant FAT1 gene, a homozygousFAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cellcarcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oraltongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngealsquamous cell carcinoma. In certain embodiments, the compound comprisesan antisense compound targeted to YAP1. In certain embodiments, thecompound comprises an oligonucleotide targeted to YAP1. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, thecompound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 23-2940. In certainembodiments, the compound comprises a modified oligonucleotide having anucleobase sequence consisting of the nucleobase sequence of any one ofSEQ ID NOs: 23-2940. In certain embodiments, the compound comprises amodified oligonucleotide consisting of 16 to 80 linked nucleosides andhaving a nucleobase sequence comprising the nucleobase sequence of anyone of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200,or 2863. In certain embodiments, the compound comprises a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864,2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 958499,1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831,or 1198872. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

In any of the foregoing methods or uses, the compound can be targeted toYAP1. In certain embodiments, the compound comprises or consists of amodified oligonucleotide, for example a modified oligonucleotideconsisting of 8 to 80 linked nucleosides, 10 to 30 linked nucleosides,12 to 30 linked nucleosides, or 20 linked nucleosides. In certainembodiments, the modified oligonucleotide is at least 80%, 85%, 90%, 95%or 100% complementary to any of the nucleobase sequences recited in SEQID NOs: 1-10. In certain embodiments, at least one internucleosidelinkage of the modified oligonucleotide is a modified internucleosidelinkage, at least one nucleoside of the modified oligonucleotidecomprises a modified sugar and/or at least one nucleobase of themodified oligonucleotide is a modified nucleobase. In certainembodiments, the modified internucleoside linkage is a phosphorothioateinternucleoside linkage, the modified sugar is a bicyclic sugar or a2′-O-methoxyethyl, and the modified nucleobase is a 5-methylcytosine. Incertain embodiments, the modified oligonucleotide has a gap segmentconsisting of linked 2′-deoxynucleosides; a 5′ wing segment consistingof linked nucleosides; and a 3′ wing segment consisting of linkednucleosides, wherein the gap segment is positioned immediately adjacentto and between the 5′ wing segment and the 3′ wing segment and whereineach nucleoside of each wing segment comprises a modified sugar.

In any of the foregoing embodiments, the modified oligonucleotide canconsist of 12 to 30, 15 to 30, 15 to 25, 15 to 24, 16 to 24, 17 to 24,18 to 24, 19 to 24, 20 to 24, 19 to 22, 20 to 22, 16 to 20, or 17 or 20linked nucleosides. In certain embodiments, the modified oligonucleotideis at least 80%, 85%, 90%, 95% or 100% complementary to any of thenucleobase sequences recited in SEQ ID NOs: 1-10. In certainembodiments, at least one internucleoside linkage of the modifiedoligonucleotide is a modified internucleoside linkage, at least onenucleoside of the modified oligonucleotide comprises a modified sugarand/or at least one nucleobase of the modified oligonucleotide is amodified nucleobase. In certain embodiments, the modifiedinternucleoside linkage is a phosphorothioate internucleoside linkage,the modified sugar is a bicyclic sugar or a 2′-O-methoxyethyl, and themodified nucleobase is a 5-methylcytosine. In certain embodiments, themodified oligonucleotide has a gap segment consisting of linked2′-deoxynucleosides; a 5′ wing segment consisting of linked nucleosides;and a 3′ wing segment consisting of linked nucleosides, wherein the gapsegment is positioned immediately adjacent to and between the 5′ wingsegment and the 3′ wing segment and wherein each nucleoside of each wingsegment comprises a modified sugar.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleosides and having a nucleobase sequence comprising the nucleobasesequence of any one of SEQ ID NOs: 23-2940, wherein the modifiedoligonucleotide has:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleobases and having a nucleobase sequence comprising the nucleobasesequence recited in any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865,1404, 1101, 2812, 1200, or 2863, wherein the modified oligonucleotidehas:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleobases and having a nucleobase sequence comprising the nucleobasesequence recited in any one of SEQ ID NOs: 810 and 1404, wherein themodified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein each internucleoside linkage is aphosphorothioate linkage; and wherein each cytosine is a5-methylcytosine. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 linked nucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleobases and having a nucleobase sequence comprising the sequencerecited in SEQ ID NO: 2864, wherein the modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein the 5′ wing segment comprises a cEtnucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethylnucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein eachinternucleoside linkage is a phosphorothioate linkage; and wherein eachcytosine is a 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleobases and having a nucleobase sequence comprising the nucleobasesequence recited in SEQ ID NOs: 1200 or 2863, wherein the modifiedoligonucleotide has:

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of the 5′ wing segmentcomprises a cEt nucleoside; wherein the 3′ wing segment comprises a cEtnucleoside, a 2′-O-methoxyethyl nucleoside, a cEt nucleoside, a2′-O-methoxyethyl nucleoside, and a cEt nucleoside in the 5′ to 3′direction; wherein each internucleoside linkage is a phosphorothioatelinkage; and wherein each cytosine is a 5-methylcytosine. In certainembodiments, the modified oligonucleotide consists of 16 to 30 linkednucleosides. In certain embodiments, the modified oligonucleotideconsists of 16 linked nucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleobases and having a nucleobase sequence comprising the nucleobasesequence recited in SEQ ID NO: 2865, wherein the modifiedoligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein the 5′ wing segment comprises a cEtnucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethylnucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein eachinternucleoside linkage is a phosphorothioate linkage; and wherein eachcytosine is a 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In any of the foregoing methods or uses, the compound can be a modifiedoligonucleotide, wherein the anion form of the modified oligonucleotidehas the following chemical structure:

or a salt thereof.

In any of the foregoing methods or uses, the compound can be a modifiedoligonucleotide according to the following chemical structure:

or a salt thereof.

In any of the foregoing methods or uses, the compound can be a modifiedoligonucleotide according to the following chemical structure:

In any of the foregoing methods or uses, the compound can beadministered parenterally. For example, in certain embodiments thecompound can be administered through injection or infusion. Parenteraladministration includes subcutaneous administration, intravenousadministration, intramuscular administration, intraarterialadministration, intraperitoneal administration, or intracranialadministration, e.g. intrathecal or intracerebroventricularadministration.

Certain Combinations and Combination Therapies

In certain embodiments, a first agent comprising a compound describedherein is co-administered with one or more secondary agents. In certainembodiments, such second agents are designed to treat the same disease,disorder, or condition as the first agent described herein. In certainembodiments, such second agents are designed to treat a differentdisease, disorder, or condition as the first agent described herein. Incertain embodiments, a first agent is designed to treat an undesiredside effect of a second agent. In certain embodiments, second agents areco-administered with the first agent to treat an undesired effect of thefirst agent. In certain embodiments, such second agents are designed totreat an undesired side effect of one or more pharmaceuticalcompositions as described herein. In certain embodiments, second agentsare co-administered with the first agent to produce a combinationaleffect. In certain embodiments, second agents are co-administered withthe first agent to produce a synergistic effect. In certain embodiments,the co-administration of the first and second agents permits use oflower dosages than would be required to achieve a therapeutic orprophylactic effect if the agents were administered as independenttherapy.

In certain embodiments, one or more compounds or compositions providedherein, such as ION 1198440, are co-administered with one or moresecondary agents. In certain embodiments, one or more compounds orcompositions provided herein and one or more secondary agents, areadministered at different times. In certain embodiments, one or morecompounds or compositions provided herein and one or more secondaryagents, are prepared together in a single formulation. In certainembodiments, one or more compounds or compositions provided herein andone or more secondary agents, are prepared separately. In certainembodiments, a secondary agent is selected from: CDK4/6 inhibitorsincluding but not limited to palbociclib, ribociclib, or abemaciclib;EGFR inhibitors including but not limited to cetuximab, necitumumab,panitumumab, vandetanib, dacomitinib, neratinib, osimertinib, gefitinib,lapatinib, or erlotinib; or kinase inhibitors including but not limitedto sorafenib, regorafenib, or carbozantinib.

Certain embodiments are directed to the use of a compound targeted toYAP1 as described herein, such as ION 1198440, in combination with asecondary agent. In particular embodiments such use is in a method oftreating a patient suffering from cancer including, but not limited to,hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma(HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamouscell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamouscell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial),esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer,tumors with mutations in SWI/SNF complex, lung cancer, non-small celllung carcinoma (NSCLC), small-cell lung carcinoma (SCLC),gastrointestinal cancer, large intestinal cancer, small intestinalcancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer,liver cancer, biliary tract cancer, urothelial cancer, breast cancer,triple-negative breast cancer (TNBC), endometrial cancer, cervicalcancer, prostate cancer, mesothelioma, chordoma, renal cancer, renalcell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skincancer, melanoma, basal cell carcinoma, merkel cell carcinoma, bloodcancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cellmalignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T celllymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certainembodiments, the cancer has a mutant FAT1 gene. In certain embodiments,the cancer has a homozygous or heterozygous FAT1 gene mutation. Incertain embodiments, the cancer having a mutant FAT1 gene, a homozygousFAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cellcarcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oraltongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngealsquamous cell carcinoma. In certain embodiments, a secondary agent isselected from: CDK4/6 inhibitors including but not limited topalbociclib, ribociclib, or abemaciclib; EGFR inhibitors including butnot limited to cetuximab, necitumumab, panitumumab, vandetanib,dacomitinib, neratinib, osimertinib, gefitinib, lapatinib, or erlotinib;or kinase inhibitors including but not limited to sorafenib,regorafenib, or carbozantinib.

Certain embodiments are drawn to a combination of a compound targeted toYAP1 as described herein, such as ION 1198440, and a secondary agent,such as CDK4/6 inhibitors including but not limited to palbociclib,ribociclib, or abemaciclib; EGFR inhibitors including but not limited tocetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib,osimertinib, gefitinib, lapatinib, or erlotinib; or kinase inhibitorsincluding but not limited to sorafenib, regorafenib, or carbozantinib.

In certain embodiments the compound targeted to YAP1 as describedherein, such as ION 1198440, and the secondary agent are used incombination treatment by administering the two agents simultaneously,separately or sequentially. In certain embodiments the two agents areformulated as a fixed dose combination product. In other embodiments thetwo agents are provided to the patient as separate units which can theneither be taken simultaneously or serially (sequentially).

In certain embodiments, a compound targeted to YAP1 as described herein,such as ION 1198440, is used in combination with an immunomodulatoryagent such as an anti-PD-L1 antibody (or an antigen-binding fragmentthereof), an anti-PD-1 antibody (or an antigen-binding fragmentthereof), an anti-CTLA-4 antibody (or an antigen-binding fragmentthereof) or an OX40 agonist ((e.g., an OX40 ligand fusion protein, or anOX40 agonist antibody or antigen-binding fragment thereof).

In certain embodiments, a compound targeted to YAP1 as described herein,such as ION 1198440, is used in combination with an immune checkpointinhibitor such as an anti-PD-L1 antibody (or an antigen-binding fragmentthereof), an anti-PD-1 antibody (or an antigen-binding fragmentthereof), or an anti-CTLA-4 antibody (or an antigen-binding fragmentthereof).

Anti-PD-L1 antibodies are known in the art. Exemplary anti-PD-L1antibodies include: MEDI4736 (durvalumab), MPDL3280A, BMS936559, 2.7A4,AMP-714, MDX-1105 and MPDL3280A (atezolizumab).

Anti-PD-1 antibodies are known in the art. Exemplary anti-PD-1antibodies include: nivolumab, pembrolizumab, pidilizumab, and AMP-514

Anti-CTLA-4 antibodies are known in the art. Exemplary anti-CTLA-4antibodies include: tremelimumab and ipilimumab, also termed MDX-010 (orBMS-734016).

OX40 agonists and antibodies are known in the art. Exemplary OX40agonists and/or antibodies include: MEDI6383, 9B12 and MEDI0562.

In one embodiment, the combination includes the antisenseoligonucleotide Ionis 1198440 or a salt thereof, and at least oneimmunomodulator selected from the group consisting of: MEDI4736,MPDL3280A, BMS936559, 2.7A4, AMP-714, MDX-1105, nivolumab,pembrolizumab, pidilizumab, MPDL3280A, tremelimumab, ipilimumab,MEDI0562 and MEDI0562.

In one embodiment, the combination includes the anti-PD-L1 antibodyMEDI4736 (duvalumab) and ION 1198440.

In one embodiment, the combination includes ION 1198440, the anti-PD-L1antibody MEDI4736 (durvalumab) and the anti-CTLA-4 antibodytremelimumab.

Certain Anti-PD-L1 Antibodies

Antibodies that specifically bind and inhibit PD-L1 are included in thepresent disclosure.

Durvalumab (MEDI4736) is an exemplary anti-PD-L1 antibody that isselective for a PD-L1 polypeptide and blocks the binding of PD-L1 to thePD-1 and CD80 receptors. Durvalumab can relieve PD-L1-mediatedsuppression of human T-cell activation in vitro and inhibits tumorgrowth in a xenograft model via a T-cell dependent mechanism.

Information regarding durvalumab (or fragments thereof) for use in themethods provided herein can be found in U.S. Pat. No. 8,779,108, thedisclosure of which is incorporated herein by reference in its entirety.The fragment crystallizable (Fc) domain of durvalumab contains a triplemutation in the constant domain of the IgG1 heavy chain that reducesbinding to the complement component C1q and the Fcγ receptorsresponsible for mediating antibody-dependent cell-mediated cytotoxicity(ADCC).

Durvalumab and antigen-binding fragments thereof for use in the methodsprovided herein comprises a heavy chain and a light chain or a heavychain variable region and a light chain variable region. In certainembodiments, MEDI4736 or an antigen-binding fragment thereof for use inthe methods provided herein comprises the variable heavy chain andvariable light chain CDR sequences of the 2.14H9OPT antibody asdisclosed in U.S. Pat. Nos. 8,779,108 and 9,493,565, which is hereinincorporated by reference in its entirety.

There are numerous anti-PD-L1 antibodies in the published literaturethat could feature in the present disclosure, including compounds indevelopment and/or in clinical trials such as: durvalumab (MEDI4736),MPDL3280A, BMS936559, 2.7A4, AMP-714 and MDX-1105. Patent specificationsdisclosing anti-PD-L1 antibodies that may be useful in the presentdisclosure include: U.S. Pat. Nos. 7,943,743; 8,383,796; 9,102,725;9,273,135 (BMS/Medarex), US2006/0153841 (Dana Farber), US2011/0271358(Dana Farber), U.S. Pat. Nos. 8,552,154 and 9,102,727 (Dana Farber),U.S. Pat. No. 8,217,149 (Genentech), including issued U.S. Pat. No.8,217,149, US2012/0039906 (INSERM), US2016/0031990 (Amplimmune), U.S.Pat. No. 8,779,108 (Medlmmune—for durvalumab/MEDI4726 and 2.7A4),US2014/0044738 (Amplimmune—for AMP-714) and US2010/0285039 (John'sHopkins University). Each of these disclosures is herein incorporated byreference in its entirety.

Certain Anti-CTLA-4 Antibodies

Antibodies that specifically bind CTLA-4 and inhibit CTLA-4 activity areuseful for enhancing an anti-tumor immune response. Informationregarding tremelimumab (or antigen-binding fragments thereof) for use inthe methods provided herein can be found in U.S. Pat. No. 6,682,736(where it is referred to as 11.2.1), the disclosure of which isincorporated herein by reference in its entirety. Tremelimumab (alsoknown as CP-675,206, CP-675, CP-675206, and ticilimumab) is a human IgG2monoclonal antibody that is highly selective for CTLA-4 and blocksbinding of CTLA-4 to CD80 (B7.1) and CD86 (B7.2). It has been shown toresult in immune activation in vitro and some patients treated withtremelimumab have shown tumor regression.

Tremelimumab for use in the methods provided herein comprises a heavychain and a light chain or a heavy chain variable region and a lightchain variable region. In a specific aspect, tremelimumab or anantigen-binding fragment thereof for use in the methods provided hereincomprises a light chain variable region comprising the amino acidsequences shown herein above and a heavy chain variable regioncomprising the amino acid sequence shown herein above. In a specificaspect, tremelimumab or an antigen-binding fragment thereof for use inthe methods provided herein comprises a heavy chain variable region anda light chain variable region, wherein the heavy chain variable regioncomprises the Kabat-defined CDR1, CDR2, and CDR3 sequences shown hereinabove, and wherein the light chain variable region comprises theKabat-defined CDR1, CDR2, and CDR3 sequences shown herein above. Thoseof ordinary skill in the art would easily be able to identifyChothia-defined, Abm-defined or other CDR definitions known to those ofordinary skill in the art. In a specific aspect, tremelimumab or anantigen-binding fragment thereof for use in the methods provided hereincomprises the variable heavy chain and variable light chain CDRsequences of the 11.2.1 antibody as disclosed in U.S. Pat. No.6,682,736, which is herein incorporated by reference in its entirety.

Other anti-CTLA-4 antibodies are described, for example, in US20070243184. In one embodiment, the anti-CTLA-4 antibody is Ipilimumab,also termed MDX-010; BMS-734016.

Certain OX40 Agonists

OX40 agonists interact with the OX40 receptor on CD4+ T-cells during, orshortly after, priming by an antigen resulting in an increased responseof the CD4+ T-cells to the antigen. An OX40 agonist interacting with theOX40 receptor on antigen specific CD4+ T-cells can increase T cellproliferation as compared to the response to antigen alone. The elevatedresponse to the antigen can be maintained for a period of timesubstantially longer than in the absence of an OX40 agonist. Thus,stimulation via an OX40 agonist enhances the antigen specific immuneresponse by boosting T-cell recognition of antigens, e.g., tumor cells.OX40 agonists are described, for example, in U.S. Pat. Nos. 6,312,700,7,504,101, 7,622,444, and 7,959,925, which are incorporated herein byreference in their entireties. Methods of using such agonists in cancertreatment are described, for example, in US2015/0098942 and inUS2015/0157710, each of which are incorporated herein by reference inits entirety.

OX40 agonists include, but are not limited to OX40 binding molecules,e.g., binding polypeptides, e.g., OX40 ligand (“OX40L”) or anOX40-binding fragment, variant, or derivative thereof, such as solubleextracellular ligand domains and OX40L fusion proteins, and anti-OX40antibodies (for example, monoclonal antibodies such as humanizedmonoclonal antibodies), or an antigen-binding fragment, variant orderivative thereof. Examples of anti-OX40 monoclonal antibodies aredescribed, for example, in U.S. Pat. Nos. 5,821,332 and 6,156,878, thedisclosures of which are incorporated herein by reference in theirentireties. In certain embodiments, the anti-OX40 monoclonal antibody is9B12, or an antigen-binding fragment, variant, or derivative thereof, asdescribed in Weinberg, A. D., et al. J Immunother 29, 575-585 (2006),which is incorporated herein by reference in its entirety. In anotherembodiment, an OX40 antibody is MEDI0562 as described in US2016/0137740.

In certain embodiments, the antibody which specifically binds to OX40,or an antigen-binding fragment thereof binds to the same OX40 epitope asmAb 9B12. An example of a humanized OX40 antibody is described by Morriset al., Mol Immunol. May 2007; 44(12): 3112-3121. 9B12 is a murine IgG1,anti-OX40 mAb directed against the extracellular domain of human OX40(CD134) (Weinberg, A. D., et al. J Immunother 29, 575-585 (2006)). Itwas selected from a panel of anti-OX40 monoclonal antibodies because ofits ability to elicit an agonist response for OX40 signaling, stability,and for its high level of production by the hybridoma. For use inclinical applications, 9B12 mAb is equilibrated with phosphate bufferedsaline, pH 7.0, and its concentration is adjusted to 5.0 mg/ml bydiafiltration.

“OX40 ligand” (“OX40L”) (also variously termed tumor necrosis factorligand superfamily member 4, gp34, TAX transcriptionally-activatedglycoprotein-1, and CD252) is found largely on antigen presenting cells(APCs), and can be induced on activated B cells, dendritic cells (DCs),Langerhans cells, plamacytoid DCs, and macrophages (Croft, M., (2010)Ann Rev Immunol 28:57-78). Other cells, including activated T cells, NKcells, mast cells, endothelial cells, and smooth muscle cells canexpress OX40L in response to inflammatory cytokines (Id.). OX40Lspecifically binds to the OX40 receptor. The human protein is describedin U.S. Pat. No. 6,156,878. The mouse OX40L is described in U.S. Pat.No. 5,457,035. OX40L is expressed on the surface of cells and includesan intracellular, a transmembrane and an extracellular receptor-bindingdomain. A functionally active soluble form of OX40L can be produced bydeleting the intracellular and transmembrane domains as described, e.g.,in U.S. Pat. Nos. 5,457,035; 6,312,700; 6,156,878; 6,242,566; 6,528,055;6,528,623; 7,098,184; and 7,125,670, the disclosures of which areincorporated herein for all purposes. A functionally active form ofOX40L is a form that retains the capacity to bind specifically to OX40,that is, that possesses an OX40 “receptor binding domain.” An example isamino acids 51 to 183 of human OX40L. Methods of determining the abilityof an OX40L molecule or derivative to bind specifically to OX40 arediscussed below. Methods of making and using OX40L and its derivatives(such as derivatives that include an OX40 binding domain) are describedin U.S. Pat. Nos. 6,156,878; 6,242,566; 6,528,055; 6,528,623; 7,098,184;and 7,125,670, which also describe proteins comprising the soluble formof OX40L linked to other peptides, such as human immunoglobulin (“Ig”)Fc regions, that can be produced to facilitate purification of OX40ligand from cultured cells, or to enhance the stability of the moleculeafter in vivo administration to a mammal (see also, U.S. Pat. Nos.5,457,035 and 7,959,925, both of which are incorporated by referenceherein in their entireties).

Also included within the definition of OX40L are OX40 ligand variantswhich vary in amino acid sequence from naturally occurring OX40 ligandmolecules but which retain the ability to specifically bind to an OX40receptor. Such variants are described in U.S. Pat. Nos. 5,457,035;6,156,878; 6,242,566; 6,528,055; 6,528,623; 7,098,184; and 7,125,670. Ina related embodiment, a mutant of OX40L which has lost the ability tospecifically bind to OX40, for example amino acids 51 to 183, in whichthe phenylalanine at position 180 of the receptor-binding domain ofhuman OX40L has been replaced with alanine (F180A) is used.

OX40 agonists include a fusion protein in which one or more domains ofOX40L is covalently linked to one or more additional protein domains.Exemplary OX40L fusion proteins that can be used as OX40 agonists aredescribed in U.S. Pat. No. 6,312,700, the disclosure of which isincorporated herein by reference in its entirety. In one embodiment, anOX40 agonist includes an OX40L fusion polypeptide that self-assemblesinto a multimeric (e.g., trimeric or hexameric) OX40L fusion protein.Such fusion proteins are described, e.g., in U.S. Pat. No. 7,959,925,which is incorporated by reference herein in its entirety. Themultimeric OX40L fusion protein exhibits increased efficacy in enhancingantigen specific immune response in a subject, particularly a humansubject, due to its ability to spontaneously assemble into highly stabletrimers and hexamers.

In another embodiment, an OX40 agonist capable of assembling into amultimeric form includes a fusion polypeptide comprising in anN-terminal to C-terminal direction: an immunoglobulin domain, whereinthe immunoglobulin domain includes an Fc domain, a trimerization domain,wherein the trimerization domain includes a coiled coil trimerizationdomain, and a receptor binding domain, wherein the receptor bindingdomain is an OX40 receptor binding domain, e.g., an OX40L or anOX40-binding fragment, variant, or derivative thereof, where the fusionpolypeptide can self-assemble into a trimeric fusion protein. In oneaspect, an OX40 agonist capable of assembling into a multimeric form iscapable of binding to the OX40 receptor and stimulating at least oneOX40 mediated activity. In certain aspects, the OX40 agonist includes anextracellular domain of OX40 ligand.

The trimerization domain of an OX40 agonist capable of assembling into amultimeric form serves to promote self-assembly of individual OX40Lfusion polypeptide molecules into a trimeric protein. Thus, an OX40Lfusion polypeptide with a trimerization domain self-assembles into atrimeric OX40L fusion protein. In one aspect, the trimerization domainis an isoleucine zipper domain or other coiled coli polypeptidestructure. Exemplary coiled coil trimerization domains include: TRAF2(GENBANK® Accession No. Q12933, amino acids 299-348; Thrombospondin 1(Accession No. PO7996, amino acids 291-314; Matrilin-4 (Accession No.O95460, amino acids 594-618; CMP (matrilin-1) (Accession No. NP-002370,amino acids 463-496; HSF1 (Accession No. AAX42211, amino acids 165-191;and Cubilin (Accession No. NP-001072, amino acids 104-138. In certainspecific aspects, the trimerization domain includes a TRAF2trimerization domain, a Matrilin-4 trimerization domain, or acombination thereof.

OX40L FP is a human OX40 ligand IgG4P fusion protein that specificallybinds to, and triggers signaling by, the human OX40 receptor, a memberof the TNFR superfamily. OX40L FP is also disclosed in US2016/0024176,incorporated herein by reference in its entirety. OX40L FP is composedof three distinct domains: (1) human OX40 ligand extracellular receptorbinding domains (RBDs) that form homotrimers and bind the OX40 receptor;(2) isoleucine zipper trimerization domains derived from TNFR-associatedfactor 2 that stabilize the homotrimeric structure of the OX40 ligandRBDs; and (3) human IgG4 fragment crystallizable gamma (Fcγ) domainsthat facilitate Fcγ receptor clustering of the fusion protein when boundto OX40 receptors, and contain a serine to proline substitution atposition 228 (according to EU numbering) in the hinge regions (IgG4P) topromote stability of two sets of OX40 ligand RBD homotrimers. The IgG4PFc domain is fused directly to an isoleucine zipper trimerization domainderived from amino acid residues 310-349 of human tumor necrosis factor2 (TRAF2). Fused to the c-terminus of the TRAF2 domain are amino acidresidues 51-183 of the extracellular receptor binding domain (RBD) ofhuman OX40L (gene name TNFSF4). The TRAF2 domain stabilizes thehomotrimeric structure of OX40L RBDs to enable OX40 binding andactivation, while the IgG4P Fc domain confers serum stability,dimerization of OX40L trimers, and facilitates Fcγ receptor clusteringof the hexameric fusion protein. One OX40L FP variant possesses aphenylalanine (F) to alanine (A) mutation at the amino acidcorresponding to position 180 in OX40L. Another OX40L FP variant has theIgG4P Fc domain replaced with a human IgG1 Fc domain. In particularembodiments, the OX40 agonist for use in the present disclosure is oneof the OX40L FP variants.

In particular embodiments, the OX40 agonist for use in the presentdisclosure has been modified to increase its serum half-life. Forexample, the serum half-life of an OX40 agonist can be increased byconjugation to a heterologous molecule such as serum albumin, anantibody Fc region, or PEG. In certain embodiments, OX40 agonists can beconjugated to other therapeutic agents or toxins to formimmunoconjugates and/or fusion proteins. In certain embodiments, theOX40 agonist can be formulated so as to facilitate administration andpromote stability of the active agent.

Antibody Derivatives

Antibodies for use in the present disclosure (e.g., anti-CTLA-4,anti-PD-L1, anti-PD-1, anti-OX40) may include variants of thesesequences that retain the ability to specifically bind their targets.Such variants may be derived from the sequence of these antibodies by askilled artisan using techniques well known in the art. For example,amino acid substitutions, deletions, or additions, can be made in theFRs and/or in the CDRs. While changes in the FRs are usually designed toimprove stability and immunogenicity of the antibody, changes in theCDRs are typically designed to increase affinity of the antibody for itstarget. Variants of FRs also include naturally occurring immunoglobulinallotypes. Such affinity-increasing changes may be determinedempirically by routine techniques that involve altering the CDR andtesting the affinity antibody for its target. For example, conservativeamino acid substitutions can be made within any one of the disclosedCDRs. Various alterations can be made according to the methods describedin Antibody Engineering, 2nd ed., Oxford University Press, ed.Borrebaeck, 1995. These include but are not limited to nucleotidesequences that are altered by the substitution of different codons thatencode a functionally equivalent amino acid residue within the sequence,thus producing a “silent” change. For example, the nonpolar amino acidsinclude alanine, leucine, isoleucine, valine, proline, phenylalanine,tryptophan, and methionine. The polar neutral amino acids includeglycine, serine, threonine, cysteine, tyrosine, asparagine, andglutamine. The positively charged (basic) amino acids include arginine,lysine, and histidine. The negatively charged (acidic) amino acidsinclude aspartic acid and glutamic acid.

Derivatives and analogs of antibodies of the present disclosure can beproduced by various techniques well known in the art, includingrecombinant and synthetic methods (Maniatis (1990) Molecular Cloning, ALaboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, Cold SpringHarbor, N.Y., and Bodansky et al. (1995) The Practice of PeptideSynthesis, 2nd ed., Spring Verlag, Berlin, Germany). Analogous shufflingor combinatorial techniques are also disclosed by Stemmer (Nature (1994)370: 389-391), who describes the technique in relation to a β-lactamasegene but observes that the approach may be used for the generation ofantibodies.

One may generate novel VH or VL regions carrying one or more sequencesderived from the sequences disclosed herein using random mutagenesis ofone or more selected VH and/or VL genes. One such technique, error-pronePCR, is described by Gram et al. (Proc. Nat. Acad. Sci. U.S.A. (1992)89: 3576-3580).

Another method that may be used is to direct mutagenesis to CDRs of VHor VL genes. Such techniques are disclosed by Barbas et al. (Proc. Nat.Acad. Sci. U.S.A. (1994) 91: 3809-3813) and Schier et al. (J. Mol. Biol.(1996) 263: 551-567).

Similarly, one or more, or all three CDRs may be grafted into arepertoire of VH or VL domains, which are then screened for anantigen-binding fragment specific for CTLA-4 or PD-L1.

A portion of an immunoglobulin variable domain will comprise at leastone of the CDRs substantially as set out herein and, optionally,intervening framework regions from the scFv fragments as set out herein.The portion may include at least about 50% of either or both of FR1 andFR4, the 50% being the C-terminal 50% of FR1 and the N-terminal 50% ofFR4. Additional residues at the N-terminal or C-terminal end of thesubstantial part of the variable domain may be those not normallyassociated with naturally occurring variable domain regions. Forexample, construction of antibodies by recombinant DNA techniques mayresult in the introduction of N- or C-terminal residues encoded bylinkers introduced to facilitate cloning or other manipulation steps.Other manipulation steps include the introduction of linkers to joinvariable domains to further protein sequences including immunoglobulinheavy chain constant regions, other variable domains (for example, inthe production of diabodies), or proteinaceous labels as discussed infurther detail below.

A skilled artisan will recognize that antibodies for use in the presentdisclosure may comprise antigen-binding fragments containing only asingle CDR from either VL or VH domain. Either one of the single chainspecific binding domains can be used to screen for complementary domainscapable of forming a two-domain specific antigen-binding fragmentcapable of, for example, binding to CTLA-4 and PD-L1.

Antibodies for use in the present disclosure described herein can belinked to another functional molecule, e.g., another peptide or protein(albumin, another antibody, etc.). For example, the antibodies can belinked by chemical cross-linking or by recombinant methods. Theantibodies may also be linked to one of a variety of nonproteinaceouspolymers, e.g., polyethylene glycol, polypropylene glycol, orpolyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835;4,496,689; 4,301,144; 4,670,417; 4,791,192; or 4,179,337. The antibodiescan be chemically modified by covalent conjugation to a polymer, forexample, to increase their circulating half-life. Exemplary polymers andmethods to attach them are also shown in U.S. Pat. Nos. 4,766,106;4,179,337; 4,495,285, and 4,609,546.

The antibodies may also be altered to have a glycosylation pattern thatdiffers from the native pattern. For example, one or more carbohydratemoieties can be deleted and/or one or more glycosylation sites added tothe original antibody. Addition of glycosylation sites to the presentlydisclosed antibodies may be accomplished by altering the amino acidsequence to contain glycosylation site consensus sequences known in theart. Another means of increasing the number of carbohydrate moieties onthe antibodies is by chemical or enzymatic coupling of glycosides to theamino acid residues of the antibody. Such methods are described in WO87/05330, and in Aplin et al. (1981) CRC Crit. Rev. Biochem., 22:259-306. Removal of any carbohydrate moieties from the antibodies may beaccomplished chemically or enzymatically, for example, as described byHakimuddin et al. (1987) Arch. Biochem. Biophys., 259: 52; and Edge etal. (1981) Anal. Biochem., 118: 131 and by Thotakura et al. (1987) Meth.Enzymol., 138: 350. The antibodies may also be tagged with a detectable,or functional, label. Detectable labels include radiolabels such as 131Ior 99Tc, which may also be attached to antibodies using conventionalchemistry. Detectable labels also include enzyme labels such ashorseradish peroxidase or alkaline phosphatase. Detectable labelsfurther include chemical moieties such as biotin, which may be detectedvia binding to a specific cognate detectable moiety, e.g., labeledavidin.

Antibodies, in which CDR sequences differ only insubstantially fromthose set forth herein are encompassed within the scope of this presentdisclosure. Typically, an amino acid is substituted by a related aminoacid having similar charge, hydrophobic, or stereochemicalcharacteristics. Such substitutions would be within the ordinary skillsof an artisan. Unlike in CDRs, more substantial changes can be made inFRs without adversely affecting the binding properties of an antibody.Changes to FRs include, but are not limited to, humanizing a non-humanderived or engineering certain framework residues that are important forantigen contact or for stabilizing the binding site, e.g., changing theclass or subclass of the constant region, changing specific amino acidresidues which might alter the effector function such as Fc receptorbinding, e.g., as described in U.S. Pat. Nos. 5,624,821 and 5,648,260and Lund et al. (1991) J. Immun. 147: 2657-2662 and Morgan et al. (1995)Immunology 86: 319-324, or changing the species from which the constantregion is derived.

One of skill in the art will appreciate that the modifications describedabove are not all-exhaustive, and that many other modifications would beobvious to a skilled artisan in light of the teachings of the presentdisclosure.

Certain Compounds

In certain embodiments, compounds described herein can be antisensecompounds. In certain embodiments, the antisense compound comprises orconsists of an oligomeric compound. In certain embodiments, theoligomeric compound comprises a modified oligonucleotide. In certainembodiments, the modified oligonucleotide has a nucleobase sequencecomplementary to that of a target nucleic acid.

In certain embodiments, a compound described herein comprises orconsists of a modified oligonucleotide. In certain embodiments, themodified oligonucleotide has a nucleobase sequence complementary to thatof a target nucleic acid.

In certain embodiments, a compound or antisense compound issingle-stranded. Such a single-stranded compound or antisense compoundcomprises or consists of an oligomeric compound. In certain embodiments,such an oligomeric compound comprises or consists of an oligonucleotideand optionally a conjugate group. In certain embodiments, theoligonucleotide is an antisense oligonucleotide. In certain embodiments,the oligonucleotide is modified. In certain embodiments, theoligonucleotide of a single-stranded antisense compound or oligomericcompound comprises a self-complementary nucleobase sequence.

In certain embodiments, compounds are double-stranded. Suchdouble-stranded compounds comprise a first modified oligonucleotidehaving a region complementary to a target nucleic acid and a secondmodified oligonucleotide having a region complementary to the firstmodified oligonucleotide. In certain embodiments, the modifiedoligonucleotide is an RNA oligonucleotide. In such embodiments, thethymine nucleobase in the modified oligonucleotide is replaced by auracil nucleobase. In certain embodiments, compound comprises aconjugate group. In certain embodiments, one of the modifiedoligonucleotides is conjugated. In certain embodiments, both themodified oligonucleotides are conjugated. In certain embodiments, thefirst modified oligonucleotide is conjugated. In certain embodiments,the second modified oligonucleotide is conjugated. In certainembodiments, the first modified oligonucleotide consists of 12-30 linkednucleosides and the second modified oligonucleotide consists of 12-30linked nucleosides. In certain embodiments, one of the modifiedoligonucleotides has a nucleobase sequence comprising at least 8contiguous nucleobases of any of SEQ ID NOs: 23-2940.

In certain embodiments, antisense compounds are double-stranded. Suchdouble-stranded antisense compounds comprise a first oligomeric compoundhaving a region complementary to a target nucleic acid and a secondoligomeric compound having a region complementary to the firstoligomeric compound. The first oligomeric compound of such doublestranded antisense compounds typically comprises or consists of amodified oligonucleotide and optionally a conjugate group. Theoligonucleotide of the second oligomeric compound of suchdouble-stranded antisense compound may be modified or unmodified. Eitheror both oligomeric compounds of a double-stranded antisense compound maycomprise a conjugate group. The oligomeric compounds of double-strandedantisense compounds may include non-complementary overhangingnucleosides.

Examples of single-stranded and double-stranded compounds include butare not limited to oligonucleotides, siRNAs, microRNA targetingoligonucleotides, and single-stranded RNAi compounds, such as smallhairpin RNAs (shRNAs), single-stranded siRNAs (ssRNAs), and microRNAmimics.

In certain embodiments, a compound described herein has a nucleobasesequence that, when written in the 5′ to 3′ direction, comprises thereverse complement of the target segment of a target nucleic acid towhich it is targeted.

In certain embodiments, a compound described herein comprises anoligonucleotide consisting of 10 to 30 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 12 to 30 linked subunits. In certain embodiments, acompound described herein comprises an oligonucleotide consisting of 12to 22 linked subunits. In certain embodiments, a compound describedherein comprises an oligonucleotide consisting of 14 to 30 linkedsubunits. In certain embodiments, compound described herein comprises anoligonucleotide consisting of 14 to 20 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 15 to 30 linked subunits. In certain embodiments, acompound described herein comprises an oligonucleotide consisting of 15to 20 linked subunits. In certain embodiments, a compound describedherein comprises an oligonucleotide consisting of 16 to 30 linkedsubunits. In certain embodiments, a compound described herein comprisesan oligonucleotide consisting of 16 to 20 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 17 to 30 linked subunits. In certain embodiments, acompound described herein comprises an oligonucleotide consisting of 17to 20 linked subunits. In certain embodiments, a compound describedherein comprises an oligonucleotide consisting of 18 to 30 linkedsubunits. In certain embodiments, a compound described herein comprisesan oligonucleotide consisting of 18 to 21 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 18 to 20 linked subunits. In certain embodiments, acompound described herein comprises an oligonucleotide consisting of 20to 30 linked subunits. In other words, such oligonucleotides consist of12 to 30 linked subunits, 14 to 30 linked subunits, 14 to 20 subunits,15 to 30 subunits, 15 to 20 subunits, 16 to 30 subunits, 16 to 20subunits, 17 to 30 subunits, 17 to 20 subunits, 18 to 30 subunits, 18 to20 subunits, 18 to 21 subunits, 20 to 30 subunits, or 12 to 22 linkedsubunits, respectively. In certain embodiments, a compound describedherein comprises an oligonucleotide consisting of 14 linked subunits. Incertain embodiments, a compound described herein comprises anoligonucleotide consisting of 16 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 17 linked subunits. In certain embodiments, compounddescribed herein comprises an oligonucleotide consisting of 18 linkedsubunits. In certain embodiments, a compound described herein comprisesan oligonucleotide consisting of 19 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 20 linked subunits. In other embodiments, a compounddescribed herein comprises an oligonucleotide consisting of 8 to 80, 12to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked subunits. Incertain such embodiments, the compound described herein comprises anoligonucleotide consisting of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, or 80 linked subunits, or a range defined byany two of the above values. In some embodiments the linked subunits arenucleotides, nucleosides, or nucleobases.

In certain embodiments, the compound may further comprise additionalfeatures or elements, such as a conjugate group, that are attached tothe oligonucleotide. In certain embodiments, such compounds areantisense compounds. In certain embodiments, such compounds areoligomeric compounds. In embodiments where a conjugate group comprises anucleoside (i.e. a nucleoside that links the conjugate group to theoligonucleotide), the nucleoside of the conjugate group is not countedin the length of the oligonucleotide.

In certain embodiments, compounds may be shortened or truncated. Forexample, a single subunit may be deleted from the 5′ end (5′truncation), or alternatively from the 3′ end (3′ truncation). Ashortened or truncated compound targeted to an YAP1 nucleic acid mayhave two subunits deleted from the 5′ end, or alternatively may have twosubunits deleted from the 3′ end, of the compound. Alternatively, thedeleted nucleosides may be dispersed throughout the compound.

When a single additional subunit is present in a lengthened compound,the additional subunit may be located at the 5′ or 3′ end of thecompound. When two or more additional subunits are present, the addedsubunits may be adjacent to each other, for example, in a compoundhaving two subunits added to the 5′ end (5′ addition), or alternativelyto the 3′ end (3′ addition), of the compound. Alternatively, the addedsubunits may be dispersed throughout the compound.

It is possible to increase or decrease the length of a compound, such asan oligonucleotide, and/or introduce mismatch bases without eliminatingactivity (Woolf et al. Proc. Natl. Acad. Sci. USA 1992, 89:7305-7309;Gautschi et al. J. Natl. Cancer Inst. March 2001, 93:463-471; Maher andDolnick Nuc. Acid. Res. 1998, 16:3341-3358). However, seemingly smallchanges in oligonucleotide sequence, chemistry and motif can make largedifferences in one or more of the many properties required for clinicaldevelopment (Seth et al. J. Med. Chem. 2009, 52, 10; Egli et al. J. Am.Chem. Soc. 2011, 133, 16642).

In certain embodiments, compounds described herein are interfering RNAcompounds (RNAi), which include double-stranded RNA compounds (alsoreferred to as short-interfering RNA or siRNA) and single-stranded RNAicompounds (or ssRNA). Such compounds work at least in part through theRISC pathway to degrade and/or sequester a target nucleic acid (thus,include microRNA/microRNA-mimic compounds). As used herein, the termsiRNA is meant to be equivalent to other terms used to describe nucleicacid molecules that are capable of mediating sequence specific RNAi, forexample short interfering RNA (siRNA), double-stranded RNA (dsRNA),micro-RNA (miRNA), short hairpin RNA (shRNA), short interferingoligonucleotide, short interfering nucleic acid, short interferingmodified oligonucleotide, chemically modified siRNA,post-transcriptional gene silencing RNA (ptgsRNA), and others. Inaddition, as used herein, the term “RNAi” is meant to be equivalent toother terms used to describe sequence specific RNA interference, such aspost transcriptional gene silencing, translational inhibition, orepigenetics.

In certain embodiments, a compound described herein can comprise any ofthe oligonucleotide sequences targeted to YAP1 described herein. Incertain embodiments, the compound can be double-stranded. In certainembodiments, the compound comprises a first strand comprising at leastan 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguousnucleobase portion of any one of SEQ ID NOs: 23-2940 and a secondstrand. In certain embodiments, the compound comprises a first strandcomprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940 anda second strand. In certain embodiments, the compound comprisesribonucleotides in which the first strand has uracil (U) in place ofthymine (T) in any one of SEQ ID NOs: 23-2940. In certain embodiments,the compound comprises (i) a first strand comprising a nucleobasesequence complementary to the site on YAP1 to which any of SEQ ID NOs:23-2940 is targeted, and (ii) a second strand. In certain embodiments,the compound comprises one or more modified nucleotides in which the 2′position in the sugar contains a halogen (such as fluorine group; 2′-F)or contains an alkoxy group (such as a methoxy group; 2′-OMe). Incertain embodiments, the compound comprises at least one 2′-F sugarmodification and at least one 2′-OMe sugar modification. In certainembodiments, the at least one 2′-F sugar modification and at least one2′-OMe sugar modification are arranged in an alternating pattern for atleast 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 contiguous nucleobases along a strand of the dsRNA compound. Incertain embodiments, the compound comprises one or more linkages betweenadjacent nucleotides other than a naturally-occurring phosphodiesterlinkage. Examples of such linkages include phosphoramide,phosphorothioate, and phosphorodithioate linkages. The compounds mayalso be chemically modified nucleic acid molecules as taught in U.S.Pat. No. 6,673,661. In other embodiments, the compound contains one ortwo capped strands, as disclosed, for example, by WO 00/63364, filedApr. 19, 2000.

In certain embodiments, the first strand of the compound is an siRNAguide strand and the second strand of the compound is an siRNA passengerstrand. In certain embodiments, the second strand of the compound iscomplementary to the first strand. In certain embodiments, each strandof the compound consists of 16, 17, 18, 19, 20, 21, 22, or 23 linkednucleosides. In certain embodiments, the first or second strand of thecompound can comprise a conjugate group.

In certain embodiments, a compound described herein can comprise any ofthe oligonucleotide sequences targeted to YAP1 described herein. Incertain embodiments, the compound is single stranded. In certainembodiments, such a compound is a single-stranded RNAi (ssRNAi)compound. In certain embodiments, the compound comprises at least an 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobaseportion of any one of SEQ ID NOs: 23-2940. In certain embodiments, thecompound comprises the nucleobase sequence of any one of SEQ ID NOs:23-2940. In certain embodiments, the compound comprises ribonucleotidesin which uracil (U) is in place of thymine (T) in any one of SEQ ID NOs:23-2940. In certain embodiments, the compound comprises a nucleobasesequence complementary to the site on YAP1 to which any of SEQ ID NOs:23-2940 is targeted. In certain embodiments, the compound comprises oneor more modified nucleotides in which the 2′ position in the sugarcontains a halogen (such as fluorine group; 2′-F) or contains an alkoxygroup (such as a methoxy group; 2′-OMe). In certain embodiments, thecompound comprises at least one 2′-F sugar modification and at least one2′-OMe sugar modification. In certain embodiments, the at least one 2′-Fsugar modification and at least one 2′-OMe sugar modification arearranged in an alternating pattern for at least 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobasesalong a strand of the compound. In certain embodiments, the compoundcomprises one or more linkages between adjacent nucleotides other than anaturally-occurring phosphodiester linkage. Examples of such linkagesinclude phosphoramide, phosphorothioate, and phosphorodithioatelinkages. The compounds may also be chemically modified nucleic acidmolecules as taught in U.S. Pat. No. 6,673,661. In other embodiments,the compound contains a capped strand, as disclosed, for example, by WO00/63364, filed Apr. 19, 2000. In certain embodiments, the compoundconsists of 16, 17, 18, 19, 20, 21, 22, or 23 linked nucleosides. Incertain embodiments, the compound can comprise a conjugate group.

In certain embodiments, compounds described herein comprise modifiedoligonucleotides. Certain modified oligonucleotides have one or moreasymmetric center and thus give rise to enantiomers, diastereomers, andother stereoisomeric configurations that may be defined, in terms ofabsolute stereochemistry, as (R) or (S), as α or β such as for sugaranomers, or as (D) or (L) such as for amino acids etc. Included in themodified oligonucleotides provided herein are all such possible isomers,including their racemic and optically pure forms, unless specifiedotherwise. Likewise, all cis- and trans-isomers and tautomeric forms arealso included.

The compounds described herein include variations in which one or moreatoms are replaced with a non-radioactive isotope or radioactive isotopeof the indicated element. For example, compounds herein that comprisehydrogen atoms encompass all possible deuterium substitutions for eachof the ¹H hydrogen atoms. Isotopic substitutions encompassed by thecompounds herein include but are not limited to: ²H or ³H in place of¹H, ¹³C or ¹⁴C in place of ¹²C, ¹⁵N in place of ¹⁴N, ¹⁷O or ¹⁸O in placeof ¹⁶O, and ³³S, ³⁴S, ³⁵S, or ³⁶S in place of ³²S. In certainembodiments, non-radioactive isotopic substitutions may impart newproperties on the compound that are beneficial for use as a therapeuticor research tool. In certain embodiments, radioactive isotopicsubstitutions may make the compound suitable for research or diagnosticpurposes, such as an imaging assay.

Certain Mechanisms

In certain embodiments, compounds described herein comprise or consistof modified oligonucleotides. In certain embodiments, compoundsdescribed herein are antisense compounds. In certain embodiments,compounds comprise oligomeric compounds. In certain embodiments,compounds described herein are capable of hybridizing to a targetnucleic acid, resulting in at least one antisense activity. In certainembodiments, compounds described herein selectively affect one or moretarget nucleic acid. Such compounds comprise a nucleobase sequence thathybridizes to one or more target nucleic acid, resulting in one or moredesired antisense activity and does not hybridize to one or morenon-target nucleic acid or does not hybridize to one or more non-targetnucleic acid in such a way that results in a significant undesiredantisense activity.

In certain antisense activities, hybridization of a compound describedherein to a target nucleic acid results in recruitment of a protein thatcleaves the target nucleic acid. For example, certain compoundsdescribed herein result in RNase H mediated cleavage of the targetnucleic acid. RNase H is a cellular endonuclease that cleaves the RNAstrand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need notbe unmodified DNA. In certain embodiments, compounds described hereinare sufficiently “DNA-like” to elicit RNase H activity. Further, incertain embodiments, one or more non-DNA-like nucleoside in the gap of agapmer is tolerated.

In certain antisense activities, compounds described herein or a portionof the compound is loaded into an RNA-induced silencing complex (RISC),ultimately resulting in cleavage of the target nucleic acid. Forexample, certain compounds described herein result in cleavage of thetarget nucleic acid by Argonaute. Compounds that are loaded into RISCare RNAi compounds. RNAi compounds may be double-stranded (siRNA) orsingle-stranded (ssRNA).

In certain embodiments, hybridization of compounds described herein to atarget nucleic acid does not result in recruitment of a protein thatcleaves that target nucleic acid. In certain such embodiments,hybridization of the compound to the target nucleic acid results inalteration of splicing of the target nucleic acid. In certainembodiments, hybridization of the compound to a target nucleic acidresults in inhibition of a binding interaction between the targetnucleic acid and a protein or other nucleic acid. In certain suchembodiments, hybridization of the compound to a target nucleic acidresults in alteration of translation of the target nucleic acid.

Antisense activities may be observed directly or indirectly. In certainembodiments, observation or detection of an antisense activity involvesobservation or detection of a change in an amount of a target nucleicacid or protein encoded by such target nucleic acid, a change in theratio of splice variants of a nucleic acid or protein, and/or aphenotypic change in a cell or animal.

Target Nucleic Acids, Target Regions and Nucleotide Sequences

In certain embodiments, compounds described herein comprise or consistof an oligonucleotide comprising a region that is complementary to atarget nucleic acid. In certain embodiments, the target nucleic acid isan endogenous RNA molecule. In certain embodiments, the target nucleicacid encodes a protein. In certain such embodiments, the target nucleicacid is selected from: an mRNA and a pre-mRNA, including intronic,exonic and untranslated regions. In certain embodiments, the target RNAis an mRNA. In certain embodiments, the target nucleic acid is apre-mRNA. In certain such embodiments, the target region is entirelywithin an intron. In certain embodiments, the target region spans anintron/exon junction. In certain embodiments, the target region is atleast 50% within an intron.

Nucleotide sequences that encode YAP1 include, without limitation, thefollowing: GENBANK or RefSEQ No. NM_001282101.1 (SEQ ID NO: 1);NC_000011.10 truncated from nucleotides 102107001 to 102236000 (SEQ IDNO: 2); NM_006106.4 (SEQ ID NO: 3); NM_001130145.2 (SEQ ID NO: 4);NM_001195044.1 (SEQ ID NO: 5); NM_001195045.1 (SEQ ID NO: 6);NM_001282097.1 (SEQ ID NO: 7); NM_001282098.1 (SEQ ID NO: 8);NM_001282099.1 (SEQ ID NO: 9); and NM_001282100.1 (SEQ ID NO: 10), eachof which is incorporated by reference in its entirety.

Hybridization

In some embodiments, hybridization occurs between a compound disclosedherein and a YAP1 nucleic acid. The most common mechanism ofhybridization involves hydrogen bonding (e.g., Watson-Crick, Hoogsteenor reversed Hoogsteen hydrogen bonding) between complementarynucleobases of the nucleic acid molecules.

Hybridization can occur under varying conditions. Hybridizationconditions are sequence-dependent and are determined by the nature andcomposition of the nucleic acid molecules to be hybridized.

Methods of determining whether a sequence is specifically hybridizableto a target nucleic acid are well known in the art. In certainembodiments, the compounds provided herein are specifically hybridizablewith a YAP1 nucleic acid.

Complementarity

An oligonucleotide is said to be complementary to another nucleic acidwhen the nucleobase sequence of such oligonucleotide or one or moreregions thereof matches the nucleobase sequence of anotheroligonucleotide or nucleic acid or one or more regions thereof when thetwo nucleobase sequences are aligned in opposing directions. Nucleobasematches or complementary nucleobases, as described herein, are limitedto the following pairs: adenine (A) and thymine (T), adenine (A) anduracil (U), cytosine (C) and guanine (G), and 5-methyl cytosine (mC) andguanine (G) unless otherwise specified. Complementary oligonucleotidesand/or nucleic acids need not have nucleobase complementarity at eachnucleoside and may include one or more nucleobase mismatches. Anoligonucleotide is fully complementary or 100% complementary when sucholigonucleotides have nucleobase matches at each nucleoside without anynucleobase mismatches.

In certain embodiments, compounds described herein comprise or consistof modified oligonucleotides. In certain embodiments, compoundsdescribed herein are antisense compounds. In certain embodiments,compounds comprise oligomeric compounds. Non-complementary nucleobasesbetween a compound and a YAP1 nucleic acid may be tolerated providedthat the compound remains able to specifically hybridize to a targetnucleic acid. Moreover, a compound may hybridize over one or moresegments of a YAP1 nucleic acid such that intervening or adjacentsegments are not involved in the hybridization event (e.g., a loopstructure, mismatch or hairpin structure).

In certain embodiments, the compounds provided herein, or a specifiedportion thereof, are, are at least, or are up to 70%, 80%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%complementary to a YAP1 nucleic acid, a target region, target segment,or specified portion thereof. In certain embodiments, the compoundsprovided herein, or a specified portion thereof, are 70% to 75%, 75% to80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or any number inbetween these ranges, complementary to a YAP1 nucleic acid, a targetregion, target segment, or specified portion thereof. Percentcomplementarity of a compound with a target nucleic acid can bedetermined using routine methods.

For example, a compound in which 18 of 20 nucleobases of the compoundare complementary to a target region, and would therefore specificallyhybridize, would represent 90 percent complementarity. In this example,the remaining non-complementary nucleobases may be clustered orinterspersed with complementary nucleobases and need not be contiguousto each other or to complementary nucleobases. As such, a compound whichconsists of 18 nucleobases having four non-complementary nucleobaseswhich are flanked by two regions of complete complementarity with thetarget nucleic acid would have 77.8% overall complementarity with thetarget nucleic acid. Percent complementarity of a compound with a regionof a target nucleic acid can be determined routinely using BLASTprograms (basic local alignment search tools) and PowerBLAST programsknown in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403 410;Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology,sequence identity or complementarity, can be determined by, for example,the Gap program (Wisconsin Sequence Analysis Package, Version 8 forUnix, Genetics Computer Group, University Research Park, Madison Wis.),using default settings, which uses the algorithm of Smith and Waterman(Adv. Appl. Math., 1981, 2, 482 489).

In certain embodiments, compounds described herein, or specifiedportions thereof, are fully complementary (i.e. 100% complementary) to atarget nucleic acid, or specified portion thereof. For example, acompound may be fully complementary to a YAP1 nucleic acid, or a targetregion, or a target segment or target sequence thereof. As used herein,“fully complementary” means each nucleobase of a compound iscomplementary to the corresponding nucleobase of a target nucleic acid.For example, a 20 nucleobase compound is fully complementary to a targetsequence that is 400 nucleobases long, so long as there is acorresponding 20 nucleobase portion of the target nucleic acid that isfully complementary to the compound. Fully complementary can also beused in reference to a specified portion of the first and/or the secondnucleic acid. For example, a 20 nucleobase portion of a 30 nucleobasecompound can be “fully complementary” to a target sequence that is 400nucleobases long. The 20 nucleobase portion of the 30 nucleobasecompound is fully complementary to the target sequence if the targetsequence has a corresponding 20 nucleobase portion wherein eachnucleobase is complementary to the 20 nucleobase portion of thecompound. At the same time, the entire 30 nucleobase compound may or maynot be fully complementary to the target sequence, depending on whetherthe remaining 10 nucleobases of the compound are also complementary tothe target sequence.

In certain embodiments, compounds described herein comprise one or moremismatched nucleobases relative to the target nucleic acid. In certainsuch embodiments, antisense activity against the target is reduced bysuch mismatch, but activity against a non-target is reduced by a greateramount. Thus, in certain such embodiments selectivity of the compound isimproved. In certain embodiments, the mismatch is specificallypositioned within an oligonucleotide having a gapmer motif. In certainsuch embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8from the 5′-end of the gap region. In certain such embodiments, themismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3′-end of thegap region. In certain such embodiments, the mismatch is at position 1,2, 3, or 4 from the 5′-end of the wing region. In certain suchembodiments, the mismatch is at position 4, 3, 2, or 1 from the 3′-endof the wing region. In certain embodiments, the mismatch is specificallypositioned within an oligonucleotide not having a gapmer motif. Incertain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, or 12 from the 5′-end of the oligonucleotide. Incertain such embodiments, the mismatch is at position, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 from the 3′-end of the oligonucleotide.

The location of a non-complementary nucleobase may be at the 5′ end or3′ end of the compound. Alternatively, the non-complementary nucleobaseor nucleobases may be at an internal position of the compound. When twoor more non-complementary nucleobases are present, they may becontiguous (i.e. linked) or non-contiguous. In one embodiment, anon-complementary nucleobase is located in the wing segment of a gapmeroligonucleotide.

In certain embodiments, compounds described herein that are, or are upto 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases in lengthcomprise no more than 4, no more than 3, no more than 2, or no more than1 non-complementary nucleobase(s) relative to a target nucleic acid,such as a YAP1 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein that are, or are upto 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, or 30 nucleobases in length comprise no more than 6, no morethan 5, no more than 4, no more than 3, no more than 2, or no more than1 non-complementary nucleobase(s) relative to a target nucleic acid,such as a YAP1 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein also include thosewhich are complementary to a portion of a target nucleic acid. As usedherein, “portion” refers to a defined number of contiguous (i.e. linked)nucleobases within a region or segment of a target nucleic acid. A“portion” can also refer to a defined number of contiguous nucleobasesof a compound. In certain embodiments, the—compounds, are complementaryto at least an 8 nucleobase portion of a target segment. In certainembodiments, the compounds are complementary to at least a 9 nucleobaseportion of a target segment. In certain embodiments, the compounds arecomplementary to at least a 10 nucleobase portion of a target segment.In certain embodiments, the compounds are complementary to at least an11 nucleobase portion of a target segment. In certain embodiments, thecompounds are complementary to at least a 12 nucleobase portion of atarget segment. In certain embodiments, the compounds are complementaryto at least a 13 nucleobase portion of a target segment. In certainembodiments, the compounds are complementary to at least a 14 nucleobaseportion of a target segment. In certain embodiments, the compounds arecomplementary to at least a 15 nucleobase portion of a target segment.In certain embodiments, the compounds are complementary to at least a 16nucleobase portion of a target segment. Also contemplated are compoundsthat are complementary to at least a 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, or more nucleobase portion of a target segment, or a rangedefined by any two of these values.

Identity

The compounds provided herein may also have a defined percent identityto a particular nucleotide sequence, SEQ ID NO, or compound representedby a specific ION number, or portion thereof. In certain embodiments,compounds described herein are antisense compounds or oligomericcompounds. In certain embodiments, compounds described herein aremodified oligonucleotides. As used herein, a compound is identical tothe sequence disclosed herein if it has the same nucleobase pairingability. For example, a RNA which contains uracil in place of thymidinein a disclosed DNA sequence would be considered identical to the DNAsequence since both uracil and thymidine pair with adenine. Shortenedand lengthened versions of the compounds described herein as well ascompounds having non-identical bases relative to the compounds providedherein also are contemplated. The non-identical bases may be adjacent toeach other or dispersed throughout the compound. Percent identity of ancompound is calculated according to the number of bases that haveidentical base pairing relative to the sequence to which it is beingcompared.

In certain embodiments, compounds described herein, or portions thereof,are, or are at least, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or 100% identical to one or more of the compounds orSEQ ID NOs, or a portion thereof, disclosed herein. In certainembodiments, compounds described herein are about 70%, 75%, 80%, 85%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical, or anypercentage between such values, to a particular nucleotide sequence, SEQID NO, or compound represented by a specific ION number, or portionthereof, in which the compounds comprise an oligonucleotide having oneor more mismatched nucleobases. In certain such embodiments, themismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 fromthe 5′-end of the oligonucleotide. In certain such embodiments, themismatch is at position, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the3′-end of the oligonucleotide.

In certain embodiments, compounds described herein comprise or consistof antisense compounds. In certain embodiments, a portion of theantisense compound is compared to an equal length portion of the targetnucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is comparedto an equal length portion of the target nucleic acid.

In certain embodiments, compounds described herein comprise or consistof oligonucleotides. In certain embodiments, a portion of theoligonucleotide is compared to an equal length portion of the targetnucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is comparedto an equal length portion of the target nucleic acid.

Certain Modified Compounds

In certain embodiments, compounds described herein comprise or consistof oligonucleotides consisting of linked nucleosides. Oligonucleotidesmay be unmodified oligonucleotides (RNA or DNA) or may be modifiedoligonucleotides. Modified oligonucleotides comprise at least onemodification relative to unmodified RNA or DNA (i.e., comprise at leastone modified nucleoside (comprising a modified sugar moiety and/or amodified nucleobase) and/or at least one modified internucleosidelinkage).

A. Modified Nucleosides

Modified nucleosides comprise a modified sugar moiety or a modifiednucleobase or both a modifed sugar moiety and a modified nucleobase.

1. Modified Sugar Moieties

In certain embodiments, sugar moieties are non-bicyclic modified sugarmoieties. In certain embodiments, modified sugar moieties are bicyclicor tricyclic sugar moieties. In certain embodiments, modified sugarmoieties are sugar surrogates. Such sugar surrogates may comprise one ormore substitutions corresponding to those of other types of modifiedsugar moieties.

In certain embodiments, modified sugar moieties are non-bicyclicmodified sugar moieties comprising a furanosyl ring with one or moreacyclic substituent, including but not limited to substituents at the2′, 4′, and/or 5′ positions. In certain embodiments one or more acyclicsubstituent of non-bicyclic modified sugar moieties is branched.Examples of 2′-substituent groups suitable for non-bicyclic modifiedsugar moieties include but are not limited to: 2′-F, 2′-OCH₃(“OMe” or“O-methyl”), and 2′-O(CH₂)₂OCH₃(“MOE”). In certain embodiments,2′-substituent groups are selected from among: halo, allyl, amino,azido, SH, CN, OCN, CF₃, OCF₃, alkoxy, O—C₁-C₁₀ substituted alkoxy,O—C₁-C₁₀ alkyl, O—C₁-C₁₀ substituted alkyl, S-alkyl, N(R_(m))-alkyl,O-alkenyl, S-alkenyl, N(R_(m))-alkenyl, O-alkynyl, S-alkynyl,N(R_(m))-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl,O-alkaryl, O-aralkyl, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)) orOCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is, independently,H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀alkyl, and the 2′-substituent groups described in Cook et al., U.S. Pat.No. 6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al.,U.S. Pat. No. 6,005,087. Certain embodiments of these 2′-substituentgroups can be further substituted with one or more substituent groupsindependently selected from among: hydroxyl, amino, alkoxy, carboxy,benzyl, phenyl, nitro (NO₂), thiol, thioalkoxy, thioalkyl, halogen,alkyl, aryl, alkenyl and alkynyl. Examples of 4′-substituent groupssuitable for linearly non-bicyclic modified sugar moieties include butare not limited to alkoxy (e.g., methoxy), alkyl, and those described inManoharan et al., WO 2015/106128. Examples of 5′-substituent groupssuitable for non-bicyclic modified sugar moieties include but are notlimited to: 5′-methyl (R or S), 5′-vinyl, and 5′-methoxy. In certainembodiments, non-bicyclic modified sugars comprise more than onenon-bridging sugar substituent, for example, 2′-F-5′-methyl sugarmoieties and the modified sugar moieties and modified nucleosidesdescribed in Migawa et al., US2010/190837 and Rajeev et al.,US2013/0203836.

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclicmodified nucleoside comprises a sugar moiety comprising a linear2′-substituent group selected from: F, NH₂, N₃, OCF₃, OCH₃, O(CH₂)₃NH₂,CH₂CH═CH₂, OCH₂CH═CH₂, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃,O(CH₂)₂ON(R_(m))(R_(n)), O(CH₂)₂O(CH₂)₂N(CH₃)₂, and N-substitutedacetamide (OCH₂C(═O)—N(R_(m))(R_(n))), where each R_(m) and R_(n) is,independently, H, an amino protecting group, or substituted orunsubstituted C₁-C₁₀ alkyl.

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclicmodified nucleoside comprises a sugar moiety comprising a linear2′-substituent group selected from: F, OCF₃, OCH₃, OCH₂CH₂OCH₃,O(CH₂)₂SCH₃, O(CH₂)₂ON(CH₃)₂, O(CH₂)₂O(CH₂)₂N(CH₃)₂, andOCH₂C(═O)—N(H)CH₃ (“NMA”).

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclicmodified nucleoside comprises a sugar moiety comprising a linear2′-substituent group selected from: F, OCH₃, and OCH₂CH₂OCH₃.

Nucleosides comprising modified sugar moieties, such as non-bicyclicmodified sugar moieties, are referred to by the position(s) of thesubstitution(s) on the sugar moiety of the nucleoside. For example,nucleosides comprising 2′-substituted or 2-modified sugar moieties arereferred to as 2′-substituted nucleosides or 2-modified nucleosides.

Certain modifed sugar moieties comprise a bridging sugar substituentthat forms a second ring resulting in a bicyclic sugar moiety. Incertain such embodiments, the bicyclic sugar moiety comprises a bridgebetween the 4′ and the 2′ furanose ring atoms. Examples of such 4′ to 2′bridging sugar substituents include but are not limited to: 4′-CH₂-2′,4′-(CH₂)₂-2′, 4′-(CH₂)₃-2′, (“LNA”), 4′-(CH₂)₂—O-2′ (“ENA”),4′-CH(CH₃)—O-2′ (referred to as “constrained ethyl” or “cEt” when in theS configuration), 4′-CH₂—O—CH₂-2′, 4′-CH₂—N(R)-2′, 4′-CH(CH₂OCH₃)—O-2′(“constrained MOE” or “cMOE”) and analogs thereof (see, e.g., Seth etal., U.S. Pat. No. 7,399,845, Bhat et al., U.S. Pat. No. 7,569,686,Swayze et al., U.S. Pat. No. 7,741,457, and Swayze et al., U.S. Pat. No.8,022,193), 4′-C(CH₃)(CH₃)—O-2′ and analogs thereof (see, e.g., Seth etal., U.S. Pat. No. 8,278,283), 4′-CH₂—N(OCH₃)-2′ and analogs thereof(see, e.g., Prakash et al., U.S. Pat. No. 8,278,425), 4′-CH₂—O—N(CH₃)-2′(see, e.g., Allerson et al., U.S. Pat. No. 7,696,345 and Allerson etal., U.S. Pat. No. 8,124,745), 4′-CH₂—C(H)(CH₃)-2′ (see, e.g., Zhou, etal., J. Org. Chem., 2009, 74, 118-134), 4′-CH₂—C(═CH₂)-2′ and analogsthereof (see e.g., Seth et al., U.S. Pat. No. 8,278,426),4′-C(R_(a)R_(b))—N(R)—O-2′, 4′-C(R_(a)R_(b))—O—N(R)-2′,4′-CH₂—O—N(R)-2′, and 4′-CH₂—N(R)—O-2′, wherein each R, R_(a), and R_(b)is, independently, H, a protecting group, or C₁-C₁₂ alkyl (see, e.g.Imanishi et al., U.S. Pat. No. 7,427,672).

In certain embodiments, such 4′ to 2′ bridges independently comprisefrom 1 to 4 linked groups independently selected from:—[C(R_(a))(R_(b))]_(n)—, —[C(R_(a))(R_(b))]_(n)—O—, —C(R_(a))═C(R_(b))—,—C(R_(a))═N—, —C(═NR_(a))—, —C(═O)—, —C(═S)—, —O—, —Si(R_(a))₂—,—S(═O)_(x)—, and —N(R_(a))—;

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R_(a) and R_(b) is, independently, H, a protecting group, hydroxyl,C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substitutedC₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl,substituted C₅-C₂₀ aryl, heterocycle radical, substituted heterocycleradical, heteroaryl, substituted heteroaryl, C₅-C₇ alicyclic radical,substituted C₅-C₇ alicyclic radical, halogen, OJ₁, NJ₁J₂, SJ₁, N₃,COOJ₁, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)₂-J₁), orsulfoxyl (S(═O)-J₁); and each J₁ and J₂ is, independently, H, C₁-C₁₂alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl,substituted C₅-C₂₀ aryl, acyl (C(═O)—H), substituted acyl, a heterocycleradical, a substituted heterocycle radical, C₁-C₁₂ aminoalkyl,substituted C₁-C₁₂ aminoalkyl, or a protecting group.

Additional bicyclic sugar moieties are known in the art, see, forexample: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443,Albaek et al., J. Org. Chem., 2006, 71, 7731-7740, Singh et al., Chem.Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54,3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A., 2000, 97,5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222;Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al.,J. Am. Chem. Soc., 2007, 129, 8362-8379; Elayadi et al., Curr. OpinionInvens. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8,1-7; Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; Wengel etal., U.S. Pat. No. 7,053,207, Imanishi et al., U.S. Pat. No. 6,268,490,Imanishi et al. U.S. Pat. No. 6,770,748, Imanishi et al., U.S. RE44,779;Wengel et al., U.S. Pat. No. 6,794,499, Wengel et al., U.S. Pat. No.6,670,461; Wengel et al., U.S. Pat. No. 7,034,133, Wengel et al., U.S.Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel etal., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582;and Ramasamy et al., U.S. Pat. No. 6,525,191, Torsten et al., WO2004/106356, Wengel et al., WO 1999/014226; Seth et al., WO 2007/134181;Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No.7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat.No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S.Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al.,U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth etal., U.S. Pat. No. 8,501,805; Allerson et al., US2008/0039618; andMigawa et al., US2015/0191727.

In certain embodiments, bicyclic sugar moieties and nucleosidesincorporating such bicyclic sugar moieties are further defined byisomeric configuration. For example, an LNA nucleoside (describedherein) may be in the α-L configuration or in the β-D configuration.

α-L-methyleneoxy (4′-CH₂—O-2′) or α-L-LNA bicyclic nucleosides have beenincorporated into oligonucleotides that showed antisense activity(Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372). Herein,general descriptions of bicyclic nucleosides include both isomericconfigurations. When the positions of specific bicyclic nucleosides(e.g., LNA or cEt) are identified in exemplified embodiments herein,they are in the β-D configuration, unless otherwise specified.

In certain embodiments, modified sugar moieties comprise one or morenon-bridging sugar substituent and one or more bridging sugarsubstituent (e.g., 5′-substituted and 4′-2′ bridged sugars).

In certain embodiments, modified sugar moieties are sugar surrogates. Incertain such embodiments, the oxygen atom of the sugar moiety isreplaced, e.g., with a sulfur, carbon or nitrogen atom. In certain suchembodiments, such modified sugar moieties also comprise bridging and/ornon-bridging substituents as described herein. For example, certainsugar surrogates comprise a 4′-sulfur atom and a substitution at the2′-position (see, e.g., Bhat et al., U.S. Pat. No. 7,875,733 and Bhat etal., U.S. Pat. No. 7,939,677) and/or the 5′ position.

In certain embodiments, sugar surrogates comprise rings having otherthan 5 atoms. For example, in certain embodiments, a sugar surrogatecomprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyransmay be further modified or substituted. Nucleosides comprising suchmodified tetrahydropyrans include but are not limited to hexitol nucleicacid (“HNA”), anitol nucleic acid (“ANA”), manitol nucleic acid (“MNA”)(see e.g., Leumann, C J. Bioorg. & Med. Chem. 2002,10, 841-854), fluoroHNA:

(“F-HNA”, see e.g., Swayze et al., U.S. Pat. No. 8,088,904; Swayze etal., U.S. Pat. No. 8,440,803; and Swayze et al., U.S. Pat. No.9,005,906, F-HNA can also be referred to as a F-THP or 3′-fluorotetrahydropyran), and nucleosides comprising additional modified THPcompounds having the formula:

wherein, independently, for each of said modified THP nucleoside:

Bx is a nucleobase moiety;

T₃ and T₄ are each, independently, an internucleoside linking grouplinking the modified THP nucleoside to the remainder of anoligonucleotide or one of T₃ and T₄ is an internucleoside linking grouplinking the modified THP nucleoside to the remainder of anoligonucleotide and the other of T₃ and T₄ is H, a hydroxyl protectinggroup, a linked conjugate group, or a 5′ or 3′-terminal group; q₁, q₂,q₃, q₄, q₅, q₆ and q₇ are each, independently, H, C₁-C₆ alkyl,substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆alkynyl, or substituted C₂-C₆ alkynyl; and each of R₁ and R₂ isindependently selected from among: hydrogen, halogen, substituted orunsubstituted alkoxy, NJ₁J₂, SJ₁, N₃, OC(═X)J₁, OC(═X)NJ₁J₂,NJ₃C(═X)NJ₁J₂, and CN, wherein X is O, S or NJ₁, and each J₁, J₂, and J₃is, independently, H or C₁-C₆ alkyl.

In certain embodiments, modified THP nucleosides are provided whereinq₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each H. In certain embodiments, atleast one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is other than H. In certainembodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is methyl. Incertain embodiments, modified THP nucleosides are provided wherein oneof R₁ and R₂ is F. In certain embodiments, R₁ is F and R₂ is H, incertain embodiments, R₁ is methoxy and R₂ is H, and in certainembodiments, R₁ is methoxyethoxy and R₂ is H.

In certain embodiments, sugar surrogates comprise rings having more than5 atoms and more than one heteroatom. For example, nucleosidescomprising morpholino sugar moieties and their use in oligonucleotideshave been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41,4503-4510 and Summerton et al., U.S. Pat. No. 5,698,685; Summerton etal., U.S. Pat. No. 5,166,315; Summerton et al., U.S. Pat. No. 5,185,444;and Summerton et al., U.S. Pat. No. 5,034,506). As used here, the term“morpholino” means a sugar surrogate having the following structure:

In certain embodiments, morpholinos may be modified, for example byadding or altering various substituent groups from the above morpholinostructure. Such sugar surrogates are refered to herein as “modifedmorpholinos.”

In certain embodiments, sugar surrogates comprise acyclic moieites.Examples of nucleosides and oligonucleotides comprising such acyclicsugar surrogates include but are not limited to: peptide nucleic acid(“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org.Biomol. Chem., 2013, 11, 5853-5865), and nucleosides andoligonucleotides described in Manoharan et al., US2013/130378.

Many other bicyclic and tricyclic sugar and sugar surrogate ring systemsare known in the art that can be used in modified nucleosides.

2. Modified Nucleobases

Nucleobase (or base) modifications or substitutions are structurallydistinguishable from, yet functionally interchangeable with, naturallyoccurring or synthetic unmodified nucleobases. Both natural and modifiednucleobases are capable of participating in hydrogen bonding. Suchnucleobase modifications can impart nuclease stability, binding affinityor some other beneficial biological property to antisense compounds.

In certain embodiments, compounds described herein comprise modifiedoligonucleotides. In certain embodiments, modified oligonucleotidescomprise one or more nucleoside comprising an unmodified nucleobase. Incertain embodiments, modified oligonucleotides comprise one or morenucleoside comprising a modified nucleobase. In certain embodiments,modified oligonucleotides comprise one or more nucleoside that does notcomprise a nucleobase, referred to as an abasic nucleoside.

In certain embodiments, modified nucleobases are selected from:5-substituted pyrimidines, 6-azapyrimi¬dines, alkyl or alkynylsubstituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6substituted purines. In certain embodiments, modified nucleobases areselected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine,5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine,6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil,2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C—CH3) uracil,5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine,5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol,8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo,particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine,2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine,3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine,4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine,5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases,promiscuous bases, size-expanded bases, and fluorinated bases. Furthermodified nucleobases include tricyclic pyrimidines, such as1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one and9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modifiednucleobases may also include those in which the purine or pyrimidinebase is replaced with other heterocycles, for example 7-deaza-adenine,7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobasesinclude those disclosed in Merigan et al., U.S. Pat. No. 3,687,808,those disclosed in The Concise Encyclopedia Of Polymer Science AndEngineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859;Englisch et al., Angewandte Chemie, International Edition, 1991, 30,613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications,Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and thosedisclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T.,Ed., CRC Press, 2008, 163-166 and 442-443.

Publications that teach the preparation of certain of the above notedmodified nucleobases as well as other modified nucleobases includewithout limitation, Manoharan et al., US2003/0158403, Manoharan et al.,US2003/0175906; Dinh et al., U.S. Pat. No. 4,845,205; Spielvogel et al.,U.S. Pat. No. 5,130,302; Rogers et al., U.S. Pat. No. 5,134,066;Bischofberger et al., U.S. Pat. No. 5,175,273; Urdea et al., U.S. Pat.No. 5,367,066; Benner et al., U.S. Pat. No. 5,432,272; Matteucci et al.,U.S. Pat. No. 5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cooket al., U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No.5,484,908; Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al.,U.S. Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540;Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat. No.5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et al., U.S.Pat. No. 5,614,617; Froehler et al., U.S. Pat. No. 5,645,985; Cook etal., U.S. Pat. No. 5,681,941; Cook et al., U.S. Pat. No. 5,811,534; Cooket al., U.S. Pat. No. 5,750,692; Cook et al., U.S. Pat. No. 5,948,903;Cook et al., U.S. Pat. No. 5,587,470; Cook et al., U.S. Pat. No.5,457,191; Matteucci et al., U.S. Pat. No. 5,763,588; Froehler et al.,U.S. Pat. No. 5,830,653; Cook et al., U.S. Pat. No. 5,808,027; Cook etal., U.S. Pat. No. 6,166,199; and Matteucci et al., U.S. Pat. No.6,005,096.

In certain embodiments, compounds targeted to a YAP1 nucleic acidcomprise one or more modified nucleobases. In certain embodiments, themodified nucleobase is 5-methylcytosine. In certain embodiments, eachcytosine is a 5-methylcytosine.

3. Modified Internucleoside Linkages

The naturally occuring internucleoside linkage of RNA and DNA is a 3′ to5′ phosphodiester linkageln certain embodiments, compounds describedherein having one or more modified, i.e. non-naturally occurring,internucleoside linkages are often selected over compounds havingnaturally occurring internucleoside linkages because of desirableproperties such as, for example, enhanced cellular uptake, enhancedaffinity for target nucleic acids, and increased stability in thepresence of nucleases.

Representative internucleoside linkages having a chiral center includebut are not limited to alkylphosphonates and phosphorothioates. Modifiedoligonucleotides comprising internucleoside linkages having a chiralcenter can be prepared as populations of modified oligonucleotidescomprising stereorandom internucleoside linkages, or as populations ofmodified oligonucleotides comprising phosphorothioate linkages inparticular stereochemical configurations. In certain embodiments,populations of modified oligonucleotides comprise phosphorothioateinternucleoside linkages wherein all of the phosphorothioateinternucleoside linkages are stereorandom. Such modifiedoligonucleotides can be generated using synthetic methods that result inrandom selection of the stereochemical configuration of eachphosphorothioate linkage. Nonetheless, as is well understood by those ofskill in the art, each individual phosphorothioate of each individualoligonucleotide molecule has a defined stereoconfiguration. In certainembodiments, populations of modified oligonucleotides are enriched formodified oligonucleotides comprising one or more particularphosphorothioate internucleoside linkages in a particular, independentlyselected stereochemical configuration. In certain embodiments, theparticular configuration of the particular phosphorothioate linkage ispresent in at least 65% of the molecules in the population. In certainembodiments, the particular configuration of the particularphosphorothioate linkage is present in at least 70% of the molecules inthe population. In certain embodiments, the particular configuration ofthe particular phosphorothioate linkage is present in at least 80% ofthe molecules in the population. In certain embodiments, the particularconfiguration of the particular phosphorothioate linkage is present inat least 90% of the molecules in the population. In certain embodiments,the particular configuration of the particular phosphorothioate linkageis present in at least 99% of the molecules in the population. Suchchirally enriched populations of modified oligonucleotides can begenerated using synthetic methods known in the art, e.g., methodsdescribed in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid.Res. 42, 13456 (2014), and WO 2017/015555. In certain embodiments, apopulation of modified oligonucleotides is enriched for modifiedoligonucleotides having at least one indicated phosphorothioate in the(Sp) configuration. In certain embodiments, a population of modifiedoligonucleotides is enriched for modified oligonucleotides having atleast one phosphorothioate in the (Rp) configuration. In certainembodiments, modified oligonucleotides comprising (Rp) and/or (Sp)phosphorothioates comprise one or more of the following formulas,respectively, wherein “B” indicates a nucleobase:

Unless otherwise indicated, chiral internucleoside linkages of modifiedoligonucleotides described herein can be stereorandom or in a particularstereochemical configuration.

In certain embodiments, compounds targeted to an YAP1 nucleic acidcomprise one or more modified internucleoside linkages. In certainembodiments, the modified internucleoside linkages are phosphorothioatelinkages. In certain embodiments, each internucleoside linkage of anantisense compound is a phosphorothioate internucleoside linkage.

In certain embodiments, compounds described herein compriseoligonucleotides. Oligonucleotides having modified internucleosidelinkages include internucleoside linkages that retain a phosphorus atomas well as internucleoside linkages that do not have a phosphorus atom.Representative phosphorus containing internucleoside linkages include,but are not limited to, phosphodiesters, phosphotriesters,methylphosphonates, phosphoramidate, and phosphorothioates. Methods ofpreparation of phosphorous-containing and non-phosphorous-containinglinkages are well known.

In certain embodiments, nucleosides of modified oligonucleotides may belinked together using any internucleoside linkage. The two main classesof internucleoside linking groups are defined by the presence or absenceof a phosphorus atom. Representative phosphorus-containinginternucleoside linkages include but are not limited to phosphates,which contain a phosphodiester bond (“P═O”) (also referred to asunmodified or naturally occurring linkages), phosphotriesters,methylphosphonates, phosphoramidates, and phosphorothioates (“P═S”), andphosphorodithioates (“HS—P═S”). Representative non-phosphorus containinginternucleoside linking groups include but are not limited tomethylenemethylimino (—CH2-N(CH3)-O—CH2-), thiodiester, thionocarbamate(—O—C(═O)(NH)—S—); siloxane (—O—SiH2-O—); and N,N′-dimethylhydrazine(—CH2-N(CH3)-N(CH3)-). Modified internucleoside linkages, compared tonaturally occurring phosphate linkages, can be used to alter, typicallyincrease, nuclease resistance of the oligonucleotide. In certainembodiments, internucleoside linkages having a chiral atom can beprepared as a racemic mixture, or as separate enantiomers.Representative chiral internucleoside linkages include but are notlimited to alkylphosphonates and phosphorothioates. Methods ofpreparation of phosphorous-containing and non-phosphorous-containinginternucleoside linkages are well known to those skilled in the art.

Neutral internucleoside linkages include, without limitation,phosphotriesters, methylphosphonates, MMI (3′-CH2-N(CH3)-O-5′), amide-3(3′-CH2-C(═O)—N(H)-5′), amide-4 (3′-CH2-N(H)—C(═O)-5′), formacetal(3′-O—CH2-O-5), methoxypropyl, and thioformacetal (3′-S—CH2-O-5′).Further neutral internucleoside linkages include nonionic linkagescomprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide,sulfide, sulfonate ester and amides (See for example: CarbohydrateModifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds.,ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutralinternucleoside linkages include nonionic linkages comprising mixed N,O, S and CH2 component parts.

In certain embodiments, oligonucleotides comprise modifiedinternucleoside linkages arranged along the oligonucleotide or regionthereof in a defined pattern or modified internucleoside linkage motif.In certain embodiments, internucleoside linkages are arranged in agapped motif. In such embodiments, the internucleoside linkages in eachof two wing regions are different from the internucleoside linkages inthe gap region. In certain embodiments the internucleoside linkages inthe wings are phosphodiester and the internucleoside linkages in the gapare phosphorothioate. The nucleoside motif is independently selected, sosuch oligonucleotides having a gapped internucleoside linkage motif mayor may not have a gapped nucleoside motif and if it does have a gappednucleoside motif, the wing and gap lengths may or may not be the same.

In certain embodiments, oligonucleotides comprise a region having analternating internucleoside linkage motif. In certain embodiments,oligonucleotides comprise a region of uniformly modified internucleosidelinkages. In certain such embodiments, the oligonucleotide comprises aregion that is uniformly linked by phosphorothioate internucleosidelinkages. In certain embodiments, the oligonucleotide is uniformlylinked by phosphorothioate. In certain embodiments, each internucleosidelinkage of the oligonucleotide is selected from phosphodiester andphosphorothioate. In certain embodiments, each internucleoside linkageof the oligonucleotide is selected from phosphodiester andphosphorothioate and at least one internucleoside linkage isphosphorothioate.

In certain embodiments, the oligonucleotide comprises at least 6phosphorothioate internucleoside linkages. In certain embodiments, theoligonucleotide comprises at least 8 phosphorothioate internucleosidelinkages. In certain embodiments, the oligonucleotide comprises at least10 phosphorothioate internucleoside linkages. In certain embodiments,the oligonucleotide comprises at least one block of at least 6consecutive phosphorothioate internucleoside linkages. In certainembodiments, the oligonucleotide comprises at least one block of atleast 8 consecutive phosphorothioate internucleoside linkages. Incertain embodiments, the oligonucleotide comprises at least one block ofat least 10 consecutive phosphorothioate internucleoside linkages. Incertain embodiments, the oligonucleotide comprises at least block of atleast one 12 consecutive phosphorothioate internucleoside linkages. Incertain such embodiments, at least one such block is located at the 3′end of the oligonucleotide. In certain such embodiments, at least onesuch block is located within 3 nucleosides of the 3′ end of theoligonucleotide.

In certain embodiments, oligonucleotides comprise one or moremethylphosponate linkages. In certain embodiments, oligonucleotideshaving a gapmer nucleoside motif comprise a linkage motif comprising allphosphorothioate linkages except for one or two methylphosponatelinkages. In certain embodiments, one methylphosponate linkage is in thecentral gap of an oligonucleotide having a gapmer nucleoside motif.

In certain embodiments, it is desirable to arrange the number ofphosphorothioate internucleoside linkages and phosphodiesterinternucleoside linkages to maintain nuclease resistance. In certainembodiments, it is desirable to arrange the number and position ofphosphorothioate internucleoside linkages and the number and position ofphosphodiester internucleoside linkages to maintain nuclease resistance.In certain embodiments, the number of phosphorothioate internucleosidelinkages may be decreased and the number of phosphodiesterinternucleoside linkages may be increased. In certain embodiments, thenumber of phosphorothioate internucleoside linkages may be decreased andthe number of phosphodiester internucleoside linkages may be increasedwhile still maintaining nuclease resistance. In certain embodiments itis desirable to decrease the number of phosphorothioate internucleosidelinkages while retaining nuclease resistance. In certain embodiments itis desirable to increase the number of phosphodiester internucleosidelinkages while retaining nuclease resistance.

Certain Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. Oligonucleotides can have a motif, e.g. a pattern ofunmodified and/or modified sugar moieties, nucleobases, and/orinternucleoside linkages. In certain embodiments, modifiedoligonucleotides comprise one or more modified nucleoside comprising amodified sugar. In certain embodiments, modified oligonucleotidescomprise one or more modified nucleosides comprising a modifiednucleobase. In certain embodiments, modified oligonucleotides compriseone or more modified internucleoside linkage. In such embodiments, themodified, unmodified, and differently modified sugar moieties,nucleobases, and/or internucleoside linkages of a modifiedoligonucleotide define a pattern or motif. In certain embodiments, thepatterns of sugar moieties, nucleobases, and internucleoside linkagesare each independent of one another. Thus, a modified oligonucleotidemay be described by its sugar motif, nucleobase motif and/orinternucleoside linkage motif (as used herein, nucleobase motifdescribes the modifications to the nucleobases independent of thesequence of nucleobases).

a. Certain Sugar Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. In certain embodiments, oligonucleotides comprise oneor more type of modified sugar and/or unmodified sugar moiety arrangedalong the oligonucleotide or region thereof in a defined pattern orsugar motif. In certain instances, such sugar motifs include but are notlimited to any of the sugar modifications discussed herein.

In certain embodiments, modified oligonucleotides comprise or consist ofa region having a gapmer motif, which comprises two external regions or“wings” and a central or internal region or “gap.” The three regions ofa gapmer motif (the 5′-wing, the gap, and the 3′-wing) form a contiguoussequence of nucleosides wherein at least some of the sugar moieties ofthe nucleosides of each of the wings differ from at least some of thesugar moieties of the nucleosides of the gap. Specifically, at least thesugar moieties of the nucleosides of each wing that are closest to thegap (the 3′-most nucleoside of the 5′-wing and the 5′-most nucleoside ofthe 3′-wing) differ from the sugar moiety of the neighboring gapnucleosides, thus defining the boundary between the wings and the gap(i.e., the wing/gap junction). In certain embodiments, the sugarmoieties within the gap are the same as one another. In certainembodiments, the gap includes one or more nucleoside having a sugarmoiety that differs from the sugar moiety of one or more othernucleosides of the gap. In certain embodiments, the sugar motifs of thetwo wings are the same as one another (symmetric gapmer). In certainembodiments, the sugar motif of the 5′-wing differs from the sugar motifof the 3′-wing (asymmetric gapmer).

In certain embodiments, the wings of a gapmer comprise 1-5 nucleosides.In certain embodiments, the wings of a gapmer comprise 2-5 nucleosides.In certain embodiments, the wings of a gapmer comprise 3-5 nucleosides.In certain embodiments, the nucleosides of a gapmer are all modifiednucleosides.

In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides.In certain embodiments, the gap of a gapmer comprises 7-10 nucleosides.In certain embodiments, the gap of a gapmer comprises 8-10 nucleosides.In certain embodiments, the gap of a gapmer comprises 10 nucleosides. Incertain embodiment, each nucleoside of the gap of a gapmer is anunmodified 2′-deoxy nucleoside.

In certain embodiments, the gapmer is a deoxy gapmer. In suchembodiments, the nucleosides on the gap side of each wing/gap junctionare unmodified 2′-deoxy nucleosides and the nucleosides on the wingsides of each wing/gap junction are modified nucleosides. In certainsuch embodiments, each nucleoside of the gap is an unmodified 2′-deoxynucleoside. In certain such embodiments, each nucleoside of each wing isa modified nucleoside.

In certain embodiments, a modified oligonucleotide has a fully modifiedsugar motif wherein each nucleoside of the modified oligonucleotidecomprises a modified sugar moiety. In certain embodiments, modifiedoligonucleotides comprise or consist of a region having a fully modifiedsugar motif wherein each nucleoside of the region comprises a modifiedsugar moiety. In certain embodiments, modified oligonucleotides compriseor consist of a region having a fully modified sugar motif, wherein eachnucleoside within the fully modified region comprises the same modifiedsugar moiety, referred to herein as a uniformly modified sugar motif. Incertain embodiments, a fully modified oligonucleotide is a uniformlymodified oligonucleotide. In certain embodiments, each nucleoside of auniformly modified comprises the same 2′-modification.

In certain embodiments, a modified oligonucleotide can comprise a sugarmotif described in Swayze et al., US2010/0197762; Freier et al.,US2014/0107330; Freier et al., US2015/0184153; and Seth et al.,US2015/0267195, each of which is incorporated by reference in itsentirety herein.

Certain embodiments provided herein are directed to modified oligomericcompounds useful for inhibiting target nucleic acid expression, whichcan be useful for treating, preventing, ameliorating, or slowingprogression of a disease associated with such a target nucleic acid. Incertain embodiments, the modified oligomeric compounds compriseantisense oligonucleotides that are gapmers having certain sugar motifs.In certain embodiments, the gapmer sugar motifs provided herein can becombined with any nucleobase sequence and any internucleoside linkagemotif to form potent antisense oligonucleotides.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: ekk-d9-kkee, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: k-d9-kekeke, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: kkk-d8-kekek, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: kkk-d9-keke, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: kk-d9-kdkdk, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 linked nucleosides and having the motif: kk-d9-eeekk,wherein ‘d’ represents a 2′-deoxyribose sugar, 1′ represents a cEtnucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certainembodiments, a method comprises contacting a cell or administering to asubject a compound comprising a modified oligonucleotide consisting of16 linked nucleosides and having the motif: kk-d9-eeekk, wherein ‘d’represents a 2′-deoxyribose sugar, 1′ represents a cEt nucleoside, and‘e’ represents a 2′-MOE nucleoside. In certain embodiments, the cell isa cancer cell. In certain embodiments, the subject has cancer. Incertain embodiments, administering the compound to the subject treatsthe subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: kk-d9-ekeke, wherein represents a 2′-deoxyribose sugar, 1′represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

b. Certain Nucleobase Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. In certain embodiments, oligonucleotides comprisemodified and/or unmodified nucleobases arranged along theoligonucleotide or region thereof in a defined pattern or motif. Incertain embodiments, each nucleobase is modified. In certainembodiments, none of the nucleobases are modified. In certainembodiments, each purine or each pyrimidine is modified. In certainembodiments, each adenine is modified. In certain embodiments, eachguanine is modified. In certain embodiments, each thymine is modified.In certain embodiments, each uracil is modified. In certain embodiments,each cytosine is modified. In certain embodiments, some or all of thecytosine nucleobases in a modified oligonucleotide are5-methylcytosines.

In certain embodiments, modified oligonucleotides comprise a block ofmodified nucleobases. In certain such embodiments, the block is at the3′-end of the oligonucleotide. In certain embodiments the block iswithin 3 nucleosides of the 3′-end of the oligonucleotide. In certainembodiments, the block is at the 5′-end of the oligonucleotide. Incertain embodiments the block is within 3 nucleosides of the 5′-end ofthe oligonucleotide.

In certain embodiments, oligonucleotides having a gapmer motif comprisea nucleoside comprising a modified nucleobase. In certain suchembodiments, one nucleoside comprising a modified nucleobase is in thecentral gap of an oligonucleotide having a gapmer motif. In certain suchembodiments, the sugar moiety of said nucleoside is a 2′-deoxyribosylmoiety. In certain embodiments, the modified nucleobase is selectedfrom: a 2-thiopyrimidine and a 5-propynepyrimidine.

c. Certain Internucleoside Linkage Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. In certain embodiments, oligonucleotides comprisemodified and/or unmodified internucleoside linkages arranged along theoligonucleotide or region thereof in a defined pattern or motif. Incertain embodiments, essentially each internucleoside linking group is aphosphate internucleoside linkage (P═O). In certain embodiments, eachinternucleoside linking group of a modified oligonucleotide is aphosphorothioate (P═S). In certain embodiments, each internucleosidelinking group of a modified oligonucleotide is independently selectedfrom a phosphorothioate and phosphate internucleoside linkage. Incertain embodiments, the sugar motif of a modified oligonucleotide is agapmer and the internucleoside linkages within the gap are all modified.In certain such embodiments, some or all of the internucleoside linkagesin the wings are unmodified phosphate linkages. In certain embodiments,the terminal internucleoside linkages are modified.

4. Certain Modified Oligonucleotides

In certain embodiments, compounds described herein comprise modifiedoligonucleotides. In certain embodiments, the above modifications(sugar, nucleobase, internucleoside linkage) are incorporated into amodified oligonucleotide. In certain embodiments, modifiedoligonucleotides are characterized by their modification, motifs, andoverall lengths. In certain embodiments, such parameters are eachindependent of one another. Thus, unless otherwise indicated, eachinternucleoside linkage of an oligonucleotide having a gapmer sugarmotif may be modified or unmodified and may or may not follow the gapmermodification pattern of the sugar modifications. For example, theinternucleoside linkages within the wing regions of a sugar gapmer maybe the same or different from one another and may be the same ordifferent from the internucleoside linkages of the gap region of thesugar motif. Likewise, such gapmer oligonucleotides may comprise one ormore modified nucleobase independent of the gapmer pattern of the sugarmodifications. Furthermore, in certain instances, an oligonucleotide isdescribed by an overall length or range and by lengths or length rangesof two or more regions (e.g., a regions of nucleosides having specifiedsugar modifications), in such circumstances it may be possible to selectnumbers for each range that result in an oligonucleotide having anoverall length falling outside the specified range. In suchcircumstances, both elements must be satisfied. For example, in certainembodiments, a modified oligonucleotide consists of 15-20 linkednucleosides and has a sugar motif consisting of three regions, A, B, andC, wherein region A consists of 2-6 linked nucleosides having aspecified sugar motif, region B consists of 6-10 linked nucleosideshaving a specified sugar motif, and region C consists of 2-6 linkednucleosides having a specified sugar motif. Such embodiments do notinclude modified oligonucleotides where A and C each consist of 6 linkednucleosides and B consists of 10 linked nucleosides (even though thosenumbers of nucleosides are permitted within the requirements for A, B,and C) because the overall length of such oligonucleotide is 22, whichexceeds the upper limit of the overall length of the modifiedoligonucleotide (20). Herein, if a description of an oligonucleotide issilent with respect to one or more parameter, such parameter is notlimited. Thus, a modified oligonucleotide described only as having agapmer sugar motif without further description may have any length,internucleoside linkage motif, and nucleobase motif. Unless otherwiseindicated, all modifications are independent of nucleobase sequence.

Certain Conjugated Compounds

In certain embodiments, the compounds described herein comprise orconsist of an oligonucleotide (modified or unmodified) and optionallyone or more conjugate groups and/or terminal groups. Conjugate groupsconsist of one or more conjugate moiety and a conjugate linker whichlinks the conjugate moiety to the oligonucleotide. Conjugate groups maybe attached to either or both ends of an oligonucleotide and/or at anyinternal position. In certain embodiments, conjugate groups are attachedto the 2′-position of a nucleoside of a modified oligonucleotide. Incertain embodiments, conjugate groups that are attached to either orboth ends of an oligonucleotide are terminal groups. In certain suchembodiments, conjugate groups or terminal groups are attached at the 3′and/or 5′-end of oligonucleotides. In certain such embodiments,conjugate groups (or terminal groups) are attached at the 3′-end ofoligonucleotides. In certain embodiments, conjugate groups are attachednear the 3′-end of oligonucleotides. In certain embodiments, conjugategroups (or terminal groups) are attached at the 5′-end ofoligonucleotides. In certain embodiments, conjugate groups are attachednear the 5′-end of oligonucleotides.

In certain embodiments, the oligonucleotide is modified. In certainembodiments, the oligonucleotide of a compound has a nucleobase sequencethat is complementary to a target nucleic acid. In certain embodiments,oligonucleotides are complementary to a messenger RNA (mRNA). In certainembodiments, oligonucleotides are complementary to a sense transcript.

Examples of terminal groups include but are not limited to conjugategroups, capping groups, phosphate moieties, protecting groups, modifiedor unmodified nucleosides, and two or more nucleosides that areindependently modified or unmodified.

A. Certain Conjugate Groups

In certain embodiments, oligonucleotides are covalently attached to oneor more conjugate groups. In certain embodiments, conjugate groupsmodify one or more properties of the attached oligonucleotide, includingbut not limited to pharmacodynamics, pharmacokinetics, stability,binding, absorption, tissue distribution, cellular distribution,cellular uptake, charge and clearanceln certain embodiments, conjugategroups impart a new property on the attached oligonucleotide, e.g.,fluorophores or reporter groups that enable detection of theoligonucleotide.

Certain conjugate groups and conjugate moieties have been describedpreviously, for example: cholesterol moiety (Letsinger et al., Proc.Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan etal., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a thioether, e.g.,hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660,306-309; Manoharan et al., Bioorg. Med. Chem. Lett., 1993, 3,2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res.,1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecylresidues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanovet al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie,1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol ortriethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate(Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al.,Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethyleneglycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14,969-973), or adamantane acetic, a palmityl moiety (Mishra et al.,Biochim. Biophys. Acta, 1995, 1264, 229-237), an octadecylamine orhexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol.Exp. Ther., 1996, i, 923-937), a tocopherol group (Nishina et al.,Molecular Therapy Nucleic Acids, 2015, 4, e220; doi:10.1038/mtna.2014.72and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or a GalNAccluster (e.g., WO2014/179620).

1. Conjugate Moieties

Conjugate moieties include, without limitation, intercalators, reportermolecules, polyamines, polyamides, peptides, carbohydrates (e.g.,GalNAc), vitamin moieties, polyethylene glycols, thioethers, polyethers,cholesterols, thiocholesterols, cholic acid moieties, folate, lipids,phospholipids, biotin, phenazine, phenanthridine, anthraquinone,adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores,and dyes.

In certain embodiments, a conjugate moiety comprises an active drugsubstance, for example, aspirin, warfarin, phenylbutazone, ibuprofen,suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen,dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid,folinic acid, a benzothiadiazide, chlorothiazide, a diazepine,indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, anantidiabetic, an antibacterial or an antibiotic.

2. Conjugate Linkers

Conjugate moieties are attached to oligonucleotides through conjugatelinkers. In certain compounds, a conjugate group is a single chemicalbond (i.e. conjugate moiety is attached to an oligonucleotide via aconjugate linker through a single bond). In certain embodiments, theconjugate linker comprises a chain structure, such as a hydrocarbylchain, or an oligomer of repeating units such as ethylene glycol,nucleosides, or amino acid units.

In certain embodiments, a conjugate linker comprises one or more groupsselected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol,ether, thioether, and hydroxylamino. In certain such embodiments, theconjugate linker comprises groups selected from alkyl, amino, oxo, amideand ether groups. In certain embodiments, the conjugate linker comprisesgroups selected from alkyl and amide groups. In certain embodiments, theconjugate linker comprises groups selected from alkyl and ether groups.In certain embodiments, the conjugate linker comprises at least onephosphorus moiety. In certain embodiments, the conjugate linkercomprises at least one phosphate group. In certain embodiments, theconjugate linker includes at least one neutral linking group.

In certain embodiments, conjugate linkers, including the conjugatelinkers described above, are bifunctional linking moieties, e.g., thoseknown in the art to be useful for attaching conjugate groups to parentcompounds, such as the oligonucleotides provided herein. In general, abifunctional linking moiety comprises at least two functional groups.One ofthe functional groups is selected to bind to a particular site ona compound and the other is selected to bind to a conjugate group.Examples of functional groups used in a bifunctional linking moietyinclude but are not limited to electrophiles for reacting withnucleophilic groups and nucleophiles for reacting with electrophilicgroups. In certain embodiments, bifunctional linking moieties compriseone or more groups selected from amino, hydroxyl, carboxylic acid,thiol, alkyl, alkenyl, and alkynyl.

Examples of conjugate linkers include but are not limited topyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include butare not limited to substituted or unsubstituted C₁-C₁₀ alkyl,substituted or unsubstituted C₂-C₁₀ alkenyl or substituted orunsubstituted C₂-C₁₀ alkynyl, wherein a nonlimiting list of preferredsubstituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl,phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl andalkynyl.

In certain embodiments, conjugate linkers comprise 1-10linker-nucleosides. In certain embodiments, such linker-nucleosides aremodified nucleosides. In certain embodiments such linker-nucleosidescomprise a modified sugar moiety. In certain embodiments,linker-nucleosides are unmodified. In certain embodiments,linker-nucleosides comprise an optionally protected heterocyclic baseselected from a purine, substituted purine, pyrimidine or substitutedpyrimidine. In certain embodiments, a cleavable moiety is a nucleosideselected from uracil, thymine, cytosine, 4-N-benzoylcytosine,5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine,6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. It is typicallydesirable for linker-nucleosides to be cleaved from the compound afterit reaches a target tissue. Accordingly, linker-nucleosides aretypically linked to one another and to the remainder of the compoundthrough cleavable bonds. In certain embodiments, such cleavable bondsare phosphodiester bonds.

Herein, linker-nucleosides are not considered to be part of theoligonucleotide. Accordingly, in embodiments in which a compoundcomprises an oligonucleotide consisting of a specified number or rangeof linked nucleosides and/or a specified percent complementarity to areference nucleic acid and the compound also comprises a conjugate groupcomprising a conjugate linker comprising linker-nucleosides, thoselinker-nucleosides are not counted toward the length of theoligonucleotide and are not used in determining the percentcomplementarity of the oligonucleotide for the reference nucleic acid.For example, a compound may comprise (1) a modified oligonucleotideconsisting of 8-30 nucleosides and (2) a conjugate group comprising 1-10linker-nucleosides that are contiguous with the nucleosides of themodified oligonucleotide. The total number of contiguous linkednucleosides in such a compound is more than 30. Alternatively, ancompound may comprise a modified oligonucleotide consisting of 8-30nucleosides and no conjugate group. The total number of contiguouslinked nucleosides in such a compound is no more than 30. Unlessotherwise indicated conjugate linkers comprise no more than 10linker-nucleosides. In certain embodiments, conjugate linkers compriseno more than 5 linker-nucleosides. In certain embodiments, conjugatelinkers comprise no more than 3 linker-nucleosides. In certainembodiments, conjugate linkers comprise no more than 2linker-nucleosides. In certain embodiments, conjugate linkers compriseno more than 1 linker-nucleoside.

In certain embodiments, it is desirable for a conjugate group to becleaved from the oligonucleotide. For example, in certain circumstancescompounds comprising a particular conjugate moiety are better taken upby a particular cell type, but once the compound has been taken up, itis desirable that the conjugate group be cleaved to release theunconjugated or parent oligonucleotide. Thus, certain conjugate maycomprise one or more cleavable moieties, typically within the conjugatelinker. In certain embodiments, a cleavable moiety is a cleavable bond.In certain embodiments, a cleavable moiety is a group of atomscomprising at least one cleavable bond. In certain embodiments, acleavable moiety comprises a group of atoms having one, two, three,four, or more than four cleavable bonds. In certain embodiments, acleavable moiety is selectively cleaved inside a cell or subcellularcompartment, such as a lysosome. In certain embodiments, a cleavablemoiety is selectively cleaved by endogenous enzymes, such as nucleases.

In certain embodiments, a cleavable bond is selected from among: anamide, an ester, an ether, one or both esters of a phosphodiester, aphosphate ester, a carbamate, or a disulfide. In certain embodiments, acleavable bond is one or both of the esters of a phosphodiester. Incertain embodiments, a cleavable moiety comprises a phosphate orphosphodiester. In certain embodiments, the cleavable moiety is aphosphate linkage between an oligonucleotide and a conjugate moiety orconjugate group.

In certain embodiments, a cleavable moiety comprises or consists of oneor more linker-nucleosides. In certain such embodiments, one or morelinker-nucleosides are linked to one another and/or to the remainder ofthe compound through cleavable bonds. In certain embodiments, suchcleavable bonds are unmodified phosphodiester bonds. In certainembodiments, a cleavable moiety is 2′-deoxy nucleoside that is attachedto either the 3′ or 5′-terminal nucleoside of an oligonucleotide by aphosphate internucleoside linkage and covalently attached to theremainder of the conjugate linker or conjugate moiety by a phosphate orphosphorothioate linkage. In certain such embodiments, the cleavablemoiety is 2′-deoxyadenosine.

Compositions and Methods for Formulating Pharmaceutical Compositions

Compounds described herein may be admixed with pharmaceuticallyacceptable active or inert substances for the preparation ofpharmaceutical compositions or formulations. Compositions and methodsfor the formulation of pharmaceutical compositions are dependent upon anumber of criteria, including, but not limited to, route ofadministration, extent of disease, or dose to be administered.

Certain embodiments provide pharmaceutical compositions comprising oneor more compounds or a salt thereof. In certain embodiments, thecompounds are antisense compounds or oligomeric compounds. In certainembodiments, the compounds comprise or consist of a modifiedoligonucleotide. In certain such embodiments, the pharmaceuticalcomposition comprises a suitable pharmaceutically acceptable diluent orcarrier. In certain embodiments, a pharmaceutical composition comprisesa sterile saline solution and one or more compound. In certainembodiments, such pharmaceutical composition consists of a sterilesaline solution and one or more compound. In certain embodiments, thesterile saline is pharmaceutical grade saline. In certain embodiments, apharmaceutical composition comprises one or more compound and sterilewater. In certain embodiments, a pharmaceutical composition consists ofone compound and sterile water. In certain embodiments, the sterilewater is pharmaceutical grade water. In certain embodiments, apharmaceutical composition comprises one or more compound andphosphate-buffered saline (PBS). In certain embodiments, apharmaceutical composition consists of one or more compound and sterilePBS. In certain embodiments, the sterile PBS is pharmaceutical gradePBS. Compositions and methods for the formulation of pharmaceuticalcompositions are dependent upon a number of criteria, including, but notlimited to, route of administration, extent of disease, or dose to beadministered.

A compound described herein targeted to YAP1 nucleic acid can beutilized in pharmaceutical compositions by combining the compound with asuitable pharmaceutically acceptable diluent or carrier. In certainembodiments, a pharmaceutically acceptable diluent is water, such assterile water suitable for injection. Accordingly, in one embodiment,employed in the methods described herein is a pharmaceutical compositioncomprising a compound targeted to YAP1 nucleic acid and apharmaceutically acceptable diluent. In certain embodiments, thepharmaceutically acceptable diluent is water. In certain embodiments,the compound comprises or consists of a modified oligonucleotideprovided herein.

Pharmaceutical compositions comprising compounds provided hereinencompass any pharmaceutically acceptable salts, esters, or salts ofsuch esters, or any other oligonucleotide which, upon administration toan animal, including a human, is capable of providing (directly orindirectly) the biologically active metabolite or residue thereof. Incertain embodiments, the compounds are antisense compounds or oligomericcompounds. In certain embodiments, the compound comprises or consists ofa modified oligonucleotide. Accordingly, for example, the disclosure isalso drawn to pharmaceutically acceptable salts of compounds, prodrugs,pharmaceutically acceptable salts of such prodrugs, and otherbioequivalents. Suitable pharmaceutically acceptable salts include, butare not limited to, sodium and potassium salts.

A prodrug can include the incorporation of additional nucleosides at oneor both ends of a compound which are cleaved by endogenous nucleaseswithin the body, to form the active compound. In certain embodiments,the compounds or compositions further comprise a pharmaceuticallyacceptable carrier or diluent.

EXAMPLES

The Examples below describe the screening process to identify leadcompounds targeted to YAP1. Out of over 3,000 oligonucleotides that werescreened, ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605,1198623, 1198728, 1198831, or 1198872 emerged as the top lead compounds.In particular, ION 1198440 exhibited the best combination of propertiesin terms of potency and tolerability out of over 3,000 oligonucleotides.

Non-Limiting Disclosure and Incorporation by Reference

Although the sequence listing accompanying this filing identifies eachsequence as either “RNA” or “DNA” as required, in reality, thosesequences may be modified with any combination of chemicalmodifications. One of skill in the art will readily appreciate that suchdesignation as “RNA” or “DNA” to describe modified oligonucleotides is,in certain instances, arbitrary. For example, an oligonucleotidecomprising a nucleoside comprising a 2′-OH sugar moiety and a thyminebase could be described as a DNA having a modified sugar (2′-OH for thenatural 2′-H of DNA) or as an RNA having a modified base (thymine(methylated uracil) for natural uracil of RNA).

Accordingly, nucleic acid sequences provided herein, including, but notlimited to those in the sequence listing, are intended to encompassnucleic acids containing any combination of natural or modified RNAand/or DNA, including, but not limited to such nucleic acids havingmodified nucleobases. By way of further example and without limitation,an oligonucleotide having the nucleobase sequence “ATCGATCG” encompassesany oligonucleotides having such nucleobase sequence, whether modifiedor unmodified, including, but not limited to, such compounds comprisingRNA bases, such as those having sequence “AUCGAUCG” and those havingsome DNA bases and some RNA bases such as “AUCGATCG” and compoundshaving other modified nucleobases, such as “AT^(m)CGAUCG,” wherein ^(m)Cindicates a cytosine base comprising a methyl group at the 5-position.

While certain compounds, compositions and methods described herein havebeen described with specificity in accordance with certain embodiments,the following examples serve only to illustrate the compounds describedherein and are not intended to limit the same. Each of the referencesrecited in the present application is incorporated herein by referencein its entirety.

Example 1 Antisense Inhibition of Human Yap1 in A-431 Cells by cEtGapmers

Modified oligonucleotides were designed to target a Yap1 nucleic acidand were tested for their effect on Yap1 mRNA level in vitro. Themodified oligonucleotides were tested in a series of experiments thathad similar culture conditions. The results for each experiment arepresented in separate tables shown below. Cultured A-431 cells at adensity of 5,000 cells per well were treated using free uptake with2,000 nM of modified oligonucleotide. After a treatment period ofapproximately 48 hours, RNA was isolated from the cells and Yap1 mRNAlevels were measured by quantitative real-time RTPCR. Human primer probeset RTS4814 (forward sequence GGGAAGTGAGCCTGTTTGGA, designated herein asSEQ ID NO.: 11; reverse sequence ACTGTTGAACAAACTAAATGCTGTGA, designatedherein as SEQ ID NO.: 12; probe sequence ATGGATGCCATTCCTTTTGCCCAGTT,designated herein as SEQ ID NO.: 13) was used to measure mRNA levels.Yap1 mRNA levels were normalized to total RNA content, as measured byRIBOGREEN®. Results are presented in the tables below as percent controlof the amount of Yap1 mRNA relative to untreated control cells (% UTC).The modified oligonucleotides with percent control values marked with anasterisk (*) target the amplicon region of the primer probe set.Additional assays may be used to measure the potency and efficacy of themodified oligonucleotides targeting the amplicon region.

The newly designed modified oligonucleotides in the Tables below weredesigned as 3-10-3 cEt gapmers. The gapmers are 16 nucleosides inlength, wherein the central gap segment comprises of ten2′-deoxynucleosides and is flanked by wing segments on the 5′ directionand the 3′ direction comprising three nucleosides each. Each nucleosidein the 5′ wing segment and each nucleoside in the 3′ wing segment has acEt sugar modification. The internucleoside linkages throughout eachgapmer are phosphorothioate (P═S) linkages. All cytosine residuesthroughout each gapmer are 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside to which the gapmer istargeted in the human gene sequence. “Stop site” indicates the 3′-mostnucleoside to which the gapmer is targeted human gene sequence. Eachgapmer listed in the Tables below is targeted to either SEQ ID NO.: 1(GENBANK Accession No. NM_001282101.1), or SEQ ID NO.: 2 (GENBANKAccession No. NC_000011.10 truncated from nucleotides 102107001 to102236000). ‘N/A’ indicates that the modified oligonucleotide does nottarget that particular gene sequence with 100% complementarity. ‘N.D.’indicates that the % UTC is not defined for that particular modifiedoligonucleotide in that particular experiment. Activity of the modifiedoligonucleotide may be defined in a different experiment.

TABLE 1Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 715400 559 574 4019 4034 CTCCGAGTCCCCGCGG 107 23 715403 658673 4118 4133 GAAGGAGTCGGGCAGC 72 24 715406 664 679 4124 4139CTTGAAGAAGGAGTCG 58 25 715409 704 719 N/A N/A CAGTACTGGCCTGTCG 76 26715412 710 725 7144 7159 CTGCATCAGTACTGGC 66 27 715415 744 759 7178 7193CGAACATGCTGTGGAG 24 28 715418 798 813 7232 7247 AGTGTCCCAGGAGAAA 126 29715421 949 964 N/A N/A GTGATTTAAGAAGTAT 71 30 715424 972 987 55467 55482TGCCATGTTGTTGTCT 58 31 715427 1081 1096 79022 79037 CCATCCATCAGGAAGA 9032 715430 1102 1117 79043 79058 ATCCTGAGTCATGGCT 118 33 715433 1133 114879074 79089 TGTTCTTATGGTTTAT 36 34 715436 1178 1193 N/A N/ATGGCAAAACGAGGGTC 126 35 715439 1184 1199 N/A N/A GGTTCATGGCAAAACG 99 36715442 1210 1225 98912 98927 CACTGGAGCACTCTGA 64 37 715445 1460 1475116649 116664 CATCCTGCTCCAGTGT 87 38 715448 1509 1524 116698 116713CTCAATTCCTGAGACA 97 39 715451 1516 1531 116705 116720 CATTGTTCTCAATTCC75 40 715454 1558 1573 N/A N/A ATAGGTGCCACTGTTA 78 41 715457 1564 1579120469 120484 AGAGTGATAGGTGCCA 47 42 715460 1570 1585 120475 120490ATCTCGAGAGTGATAG 114 43 715463 1608 1623 120513 120528 CTGTAGCTGCTCATGC73 44 715466 1751 1766 122776 122791 CAAGGTCCACATTTGT 83 45 715469 18701885 122895 122910 TAGCTTGGTGGCAGCC 94 46 715472 1876 1891 122901 122916TTTATCTAGCTTGGTG 52 47 715475 1883 1898 122908 122923 AGCTTTCTTTATCTAG103 48 715478 3560 3575 124585 124600 ACCATTATTACTCCTG 7 49 715481 35663581 124591 124606 TTGGAAACCATTATTA 66 50 715484 3572 3587 101152 101167TACTCTTTGGAAACCA 123 51 124597 124612 715487 3630 3645 124655 124670ATTACTTCATAGCTTA 22 52 715490 3636 3651 124661 124676 CCAACTATTACTTCAT38 53 715493 3665 3680 124690 124705 GTGCTAGCTGGTGCCA 62 54 715496 37203735 124745 124760 CCCTTGAAAATAAGGG 124 55 715499 3726 3741 124751124766 TATGAACCCTTGAAAA 126 56 715502 4011 4026 125036 125051CCAGACTTAATTCAAG 91 57 715505 4684 4699 125709 125724 ATTGGTTTATTGTAAA84 58 715508 1397 1412 102529 102544 CTGTGCTGGGATTGAT 24 59 715511 14191434 N/A N/A TCCTGACATTTTGGAG 107 60 715514 N/A N/A 4573 4588GAGCGAAGGTGCGGAG 121 61 715517 N/A N/A 5151 5166 GGCCTATGAGTCAACC 109 62715520 N/A N/A 5544 5559 TTCTTTCCACTCAAGT 122 63 715523 N/A N/A 71407155 ATCAGTACTGGCCTAT 32 64 715526 N/A N/A 7385 7400 ACTTACTTTAAGAAGT112 65 715529 N/A N/A 8646 8661 TGAAACCTGATCCTTT 148 66 715532 N/A N/A8820 8835 TAACAACCTGGTTTGT 91 67 715535 N/A N/A 8906 8921CTATTAAGCTGTTTAA 91 68 715538 N/A N/A 10383 10398 CTTTGTAACTTAAAAG 11069 715541 N/A N/A 10918 10933 CTTGAAGAACTATTTC 105 70 715544 N/A N/A10924 10939 CAACTACTTGAAGAAC 128 71 715547 N/A N/A 10930 10945GTTGACCAACTACTTG 98 72 715550 N/A N/A 10938 10953 AGGAAGTTGTTGACCA 70 73715553 N/A N/A 10944 10959 AGAAATAGGAAGTTGT 90 74 715556 N/A N/A 1096510980 AAGTTATTCAGCAGCT 63 75 715559 N/A N/A 28556 28571 CTGCCATTTAAGAAAT114 76 715562 N/A N/A 37601 37616 CACACAACTCAGACAG 77 77 715565 N/A N/A37826 37841 GGATAAATGAATTATA 115 78 715568 N/A N/A 37832 37847AAGGTAGGATAAATGA 116 79 715571 N/A N/A 105518 105533 AAAATCCTGCCAACAT127 80 715574 N/A N/A 79119 79134 TACCAAAACGAGGGTC 118 81 715577 N/A N/A80085 80100 GCATTCACAGAGTTAA 21 82 715580 N/A N/A 80919 80934GCCTGTCTGGAATACA 101 83 715583 N/A N/A 80954 80969 GGGCCACAAAATAAAA 16484 715586 N/A N/A 80980 80995 AAAAGGTCTGGAACAG 53 85 715589 N/A N/A81086 81101 CCAGCAGCTAACAGCT 107 86 715592 N/A N/A 81151 81166TTCTTTGGCAGAGATA 89 87 715595 N/A N/A 98883 98898 TCATGGCTGAAATGAA 10488 715598 N/A N/A 102395 102410 CCCAAGCTACCCAAGA 103 89 715601 N/A N/A102401 102416 AGAATTCCCAAGCTAC 106 90 715604 N/A N/A 102407 102422TAGCACAGAATTCCCA 107 91 715607 N/A N/A 102413 102428 TCACCATAGCACAGAA116 92 715610 N/A N/A 102451 102466 GGCTGTGTAGGCTGAC 87 93 715613 N/AN/A 102473 102488 ATTACTTTAAGCCACA 85 94 715616 N/A N/A 102484 102499GACGGATAAAAATTAC 95 95 715619 N/A N/A 102490 102505 AAATAAGACGGATAAA 11496 715622 N/A N/A 102496 102511 AGTAAAAAATAAGACG 137 97 715625 N/A N/A102506 102521 ATTGCCTAAGAGTAAA 99 98 715628 N/A N/A 102555 102570GCCTACCTGACATTTT 114 99 715631 N/A N/A 102561 102576 ATAAGAGCCTACCTGA134 100

TABLE 2Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 715401 562 577 4022 4037 GGTCTCCGAGTCCCCG 84 101 715404 660675 4120 4135 AAGAAGGAGTCGGGCA 64 102 715407 666 681 4126 4141GGCTTGAAGAAGGAGT 53 103 715410 706 721 N/A N/A ATCAGTACTGGCCTGT 61 104715413 740 755 7174 7189 CATGCTGTGGAGTCAG 96 105 715416 746 761 71807195 CTCGAACATGCTGTGG 53 106 715419 929 944 7363 7378 GACCAGAAGATGTCTT107 107 715422 968 983 55463 55478 ATGTTGTTGTCTGATC 57 108 715425 976991 55471 55486 GTCCTGCCATGTTGTT 98 109 715428 1083 1098 79024 79039TCCCATCCATCAGGAA 106 110 715431 1104 1119 79045 79060 CCATCCTGAGTCATGG99 111 715434 1136 1151 79077 79092 TCTTGTTCTTATGGTT 31 112 715437 11801195 N/A N/A CATGGCAAAACGAGGG 89 113 715440 1186 1201 N/A N/ACTGGTTCATGGCAAAA 85 114 715443 1212 1227 98914 98929 TTCACTGGAGCACTCT 40115 715446 1505 1520 116694 116709 ATTCCTGAGACATCCC 81 116 715449 15111526 116700 116715 TTCTCAATTCCTGAGA 124 117 715452 1518 1533 116707116722 GTCATTGTTCTCAATT 71 118 715455 1560 1575 N/A N/A TGATAGGTGCCACTGT65 119 715458 1566 1581 120471 120486 CGAGAGTGATAGGTGC 58 120 7154611572 1587 120477 120492 TCATCTCGAGAGTGAT 153 121 715464 1745 1760 122770122785 CCACATTTGTCCCAGG 89 122 715467 1769 1784 122794 122809CATCTCCTTCCAGTGT 77 123 715470 1872 1887 122897 122912 TCTAGCTTGGTGGCAG83 124 715473 1878 1893 122903 122918 TCTTTATCTAGCTTGG 32 125 7154761885 1900 122910 122925 AAAGCTTTCTTTATCT 84 126 715479 3562 3577 124587124602 AAACCATTATTACTCC 38 127 715482 3568 3583 124593 124608CTTTGGAAACCATTAT 58 128 715485 3574 3589 124599 124614 AATACTCTTTGGAAAC72 129 715488 3632 3647 124657 124672 CTATTACTTCATAGCT 66 130 7154913638 3653 124663 124678 AACCAACTATTACTTC 71 131 715494 3668 3683 124693124708 GAGGTGCTAGCTGGTG 46 132 715497 3722 3737 124747 124762AACCCTTGAAAATAAG 155 133 715500 3966 3981 11043 11058 AAGCCTTAGAGTCAAT30 134 124991 125006 715503 4013 4028 125038 125053 CCCCAGACTTAATTCA 136135 715506 4686 4701 125711 125726 AAATTGGTTTATTGTA 112 136 715509 13991414 102531 102546 TGCTGTGCTGGGATTG 42 137 715512 N/A N/A 4550 4565AGGCGCGCGCATTGTG 97 138 715515 N/A N/A 5147 5162 TATGAGTCAACCTGCA 94 139715518 N/A N/A 5477 5492 TTTGGGCAAAGTTCCT 60 140 715521 N/A N/A 55465561 TCTTCTTTCCACTCAA 72 141 715524 N/A N/A 7381 7396 ACTTTAAGAAGTATCT93 142 715527 N/A N/A 7387 7402 TCACTTACTTTAAGAA 111 143 715530 N/A N/A8816 8831 AACCTGGTTTGTTTCC 61 144 715533 N/A N/A 8822 8837CCTAACAACCTGGTTT 97 145 715536 N/A N/A 8908 8923 GGCTATTAAGCTGTTT 137146 715539 N/A N/A 10637 10652 AGATCTCACTGACCTA 102 147 715542 N/A N/A10920 10935 TACTTGAAGAACTATT 120 148 715545 N/A N/A 10926 10941ACCAACTACTTGAAGA 87 149 715548 N/A N/A 10934 10949 AGTTGTTGACCAACTA 117150 715551 N/A N/A 10940 10955 ATAGGAAGTTGTTGAC 82 151 715554 N/A N/A10961 10976 TATTCAGCAGCTTATA 93 152 715557 N/A N/A 10967 10982GGAAGTTATTCAGCAG 46 153 715560 N/A N/A 37563 37578 CCCTTTACAAAAATAG 98154 715563 N/A N/A 37603 37618 AGCACACAACTCAGAC 86 155 715566 N/A N/A37828 37843 TAGGATAAATGAATTA 94 156 715569 N/A N/A 37834 37849CAAAGGTAGGATAAAT 122 157 715572 N/A N/A 78867 78882 TCAGAGAAGAAAGGTA 97158 715575 N/A N/A 79123 79138 CCTTTACCAAAACGAG 134 159 715578 N/A N/A80087 80102 TGGCATTCACAGAGTT 50 160 715581 N/A N/A 80921 80936AAGCCTGTCTGGAATA 106 161 715584 N/A N/A 80976 80991 GGTCTGGAACAGATTA 96162 715587 N/A N/A 80982 80997 TGAAAAGGTCTGGAAC 79 163 715590 N/A N/A81147 81162 TTGGCAGAGATAAAAC 84 164 715593 N/A N/A 81153 81168ATTTCTTTGGCAGAGA 60 165 715596 N/A N/A 98885 98900 GTTCATGGCTGAAATG 104166 715599 N/A N/A 102397 102412 TTCCCAAGCTACCCAA 82 167 715602 N/A N/A102403 102418 ACAGAATTCCCAAGCT 110 168 715605 N/A N/A 102409 102424CATAGCACAGAATTCC 112 169 715608 N/A N/A 102430 102445 AATTGTATCCAGACAT100 170 715611 N/A N/A 102469 102484 CTTTAAGCCACATGGT 106 171 715614 N/AN/A 102475 102490 AAATTACTTTAAGCCA 110 172 715617 N/A N/A 102486 102501AAGACGGATAAAAATT 98 173 715620 N/A N/A 102492 102507 AAAAATAAGACGGATA111 174 715623 N/A N/A 102502 102517 CCTAAGAGTAAAAAAT 113 175 715626 N/AN/A 102551 102566 ACCTGACATTTTGGAG 64 176 715629 N/A N/A 102557 102572GAGCCTACCTGACATT 112 177 715632 N/A N/A 109609 109624 ATCCAATTATGTCCCA109 178

TABLE 3Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 715402 656 671 4116 4131 AGGAGTCGGGCAGCTT 59 179 715405 662677 4122 4137 TGAAGAAGGAGTCGGG 60 180 715408 668 683 4128 4143GCGGCTTGAAGAAGGA 60 181 715411 708 723 7142 7157 GCATCAGTACTGGCCT 94 182715414 742 757 7176 7191 AACATGCTGTGGAGTC 31 183 715417 749 764 71837198 GAGCTCGAACATGCTG 104 184 715420 947 962 N/A N/A GATTTAAGAAGTATCT107 185 715423 970 985 55465 55480 CCATGTTGTTGTCTGA 30 186 715426 10791094 79020 79035 ATCCATCAGGAAGAGG 80 187 715429 1100 1115 79041 79056CCTGAGTCATGGCTTG 62 188 715432 1106 1121 79047 79062 CTCCATCCTGAGTCAT 65189 715435 1138 1153 79079 79094 GGTCTTGTTCTTATGG 36 190 715438 11821197 N/A N/A TTCATGGCAAAACGAG 82 191 715441 1188 1203 N/A N/ACTCTGGTTCATGGCAA 57 192 715444 1249 1264 98951 98966 TCCCTGTGGGCTCTGG 84193 715447 1507 1522 116696 116711 CAATTCCTGAGACATC 81 194 715450 15141529 116703 116718 TTGTTCTCAATTCCTG 53 195 715453 1556 1571 N/A N/AAGGTGCCACTGTTAAG 59 196 715456 1562 1577 120467 120482 AGTGATAGGTGCCACT96 197 715459 1568 1583 120473 120488 CTCGAGAGTGATAGGT 93 198 7154621574 1589 120479 120494 TCTCATCTCGAGAGTG 94 199 715465 1747 1762 122772122787 GTCCACATTTGTCCCA 91 200 715468 1868 1883 122893 122908GCTTGGTGGCAGCCAA 90 201 715471 1874 1889 122899 122914 TATCTAGCTTGGTGGC36 202 715474 1881 1896 122906 122921 CTTTCTTTATCTAGCT 78 203 7154773543 3558 124568 124583 AGACACATACTCTAGT 61 204 715480 3564 3579 124589124604 GGAAACCATTATTACT 23 205 715483 3570 3585 124595 124610CTCTTTGGAAACCATT 15 206 715486 3628 3643 124653 124668 TACTTCATAGCTTATA27 207 715489 3634 3649 124659 124674 AACTATTACTTCATAG 90 208 7154923663 3678 124688 124703 GCTAGCTGGTGCCACT 76 209 715495 3671 3686 124696124711 ACAGAGGTGCTAGCTG 80 210 715498 3724 3739 124749 124764TGAACCCTTGAAAATA 91 211 715501 3968 3983 64588 64603 AAAAGCCTTAGAGTCA 28212 124993 125008 715504 4682 4697 125707 125722 TGGTTTATTGTAAAAG 70 213715507 1391 1406 102523 102538 TGGGATTGATATTCCG 95 214 715510 1402 1417102534 102549 ATTTGCTGTGCTGGGA 22 215 715513 N/A N/A 4554 4569GCGGAGGCGCGCGCAT 125 216 715516 N/A N/A 5149 5164 CCTATGAGTCAACCTG 77217 715519 N/A N/A 5540 5555 TTCCACTCAAGTTACA 96 218 715522 N/A N/A 55485563 ACTCTTCTTTCCACTC 87 219 715525 N/A N/A 7383 7398 TTACTTTAAGAAGTAT100 220 715528 N/A N/A 8644 8659 AAACCTGATCCTTTGA 98 221 715531 N/A N/A8818 8833 ACAACCTGGTTTGTTT 94 222 715534 N/A N/A 8885 8900TCCCCAGGTCAGCATG 112 223 715537 N/A N/A 10155 10170 ACTTGGCACCAAAAGC 122224 715540 N/A N/A 10916 10931 TGAAGAACTATTTCCT 82 225 715543 N/A N/A10922 10937 ACTACTTGAAGAACTA 72 226 715546 N/A N/A 10928 10943TGACCAACTACTTGAA 59 227 715549 N/A N/A 10936 10951 GAAGTTGTTGACCAAC 66228 715552 N/A N/A 10942 10957 AAATAGGAAGTTGTTG 86 229 715555 N/A N/A10963 10978 GTTATTCAGCAGCTTA 21 230 715558 N/A N/A 10969 10984CAGGAAGTTATTCAGC 37 231 715561 N/A N/A 37599 37614 CACAACTCAGACAGGG 69232 715564 N/A N/A 37605 37620 CAAGCACACAACTCAG 75 233 715567 N/A N/A37830 37845 GGTAGGATAAATGAAT 99 234 715570 N/A N/A 37836 37851GCCAAAGGTAGGATAA 79 235 715573 N/A N/A 64347 64362 TATATATGGTAGTCTA 76236 715576 N/A N/A 79125 79140 AACCTTTACCAAAACG 80 237 715579 N/A N/A80917 80932 CTGTCTGGAATACACA 100 238 715582 N/A N/A 80924 80939GTCAAGCCTGTCTGGA 33 239 715585 N/A N/A 80978 80993 AAGGTCTGGAACAGAT 73240 715588 N/A N/A 81084 81099 AGCAGCTAACAGCTTG 96 241 715591 N/A N/A81149 81164 CTTTGGCAGAGATAAA 41 242 715594 N/A N/A 81155 81170ATATTTCTTTGGCAGA 39 243 715597 N/A N/A 98888 98903 CTGGTTCATGGCTGAA 89244 715600 N/A N/A 102399 102414 AATTCCCAAGCTACCC 82 245 715603 N/A N/A102405 102420 GCACAGAATTCCCAAG 106 246 715606 N/A N/A 102411 102426ACCATAGCACAGAATT 88 247 715609 N/A N/A 102448 102463 TGTGTAGGCTGACTTA 56248 715612 N/A N/A 102471 102486 TACTTTAAGCCACATG 77 249 715615 N/A N/A102482 102497 CGGATAAAAATTACTT 94 250 715618 N/A N/A 102488 102503ATAAGACGGATAAAAA 101 251 715621 N/A N/A 102494 102509 TAAAAAATAAGACGGA106 252 715624 N/A N/A 102504 102519 TGCCTAAGAGTAAAAA 123 253 715627 N/AN/A 102553 102568 CTACCTGACATTTTGG 88 254 715630 N/A N/A 102559 102574AAGAGCCTACCTGACA 94 255 715633 N/A N/A 120466 120481 GTGATAGGTGCCACTA 78256

Example 2 Antisense Inhibition of Human Yap1 in A-431 Cells by cEtGapmers

Modified oligonucleotides were designed to target a Yap1 nucleic acidand were tested for their effect on Yap1 mRNA level in vitro. Themodified oligonucleotides were tested in a series of experiments thathad similar culture conditions. The results for each experiment arepresented in separate tables shown below. Cultured A-431 cells at adensity of 5,000 cells per well were treated using free uptake with2,000 nM of modified oligonucleotide. After a treatment period ofapproximately 48 hours, RNA was isolated from the cells and Yap1 mRNAlevels were measured by quantitative real-time RTPCR. Human primer probeset RTS4814 was used to measure mRNA levels. Yap1 mRNA levels werenormalized to total RNA content, as measured by RIBOGREEN®. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC). The modifiedoligonucleotides with percent control values marked with an asterisk (*)target the amplicon region of the primer probe set. Additional assaysmay be used to measure the potency and efficacy of the modifiedoligonucleotides targeting the amplicon region.

The newly designed modified oligonucleotides in the Tables below weredesigned as 3-10-3 cEt gapmers. The gapmers are 16 nucleosides inlength, wherein the central gap segment comprises of ten2′-deoxynucleosides and is flanked by wing segments on the 5′ directionand the 3′ direction comprising three nucleosides each. Each nucleosidein the 5′ wing segment and each nucleoside in the 3′ wing segment has acEt sugar modification. The internucleoside linkages throughout eachgapmer are phosphorothioate (P═S) linkages. All cytosine residuesthroughout each gapmer are 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside to which the gapmer istargeted in the human gene sequence. “Stop site” indicates the 3′-mostnucleoside to which the gapmer is targeted human gene sequence. Gapmerslisted in the Tables below are targeted to either SEQ ID NO: 1, SEQ IDNO: 2, SEQ ID NO: 3 (GENBANK Accession No. NM_006106.4), or SEQ ID NO: 4(GENBANK Accession No. NM_001130145.2). ‘N/A’ indicates that themodified oligonucleotide does not target that particular gene sequencewith 100% complementarity. ‘N.D.’ indicates that the % UTC is notdefined for that particular modified oligonucleotide in that particularexperiment. Activity ofthe modified oligonucleotide may be defined in adifferent experiment.

TABLE 4Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 716346 1 16 3461 3476 TTTCCCTGGCGGCGGC 77 257 716349 107 1223567 3582 ACTTTTTCCCTCCAAC 78 258 716352 184 199 3644 3659CTGCGCCCCGGCTCCA 105 259 716355 279 294 3739 3754 GACGGCTGCGGGCCGG 96260 716358 331 346 3791 3806 CGAGGGCTACGCCCGG 104 261 716361 405 4203865 3880 GGTTGAGGCGGCGGCT 75 262 716364 493 508 3953 3968CGCCGCGGGTGCCGGT 110 263 716367 631 646 4091 4106 CATGGGCACGGTCTGG 70264 716370 716 731 7150 7165 CAGTGCCTGCATCAGT 25 265 716373 775 790 72097224 CAACTGCAGAGAAGCT 69 266 716376 855 870 7289 7304 CGAAGATGCTGAGCTG35 267 716379 927 942 7361 7376 CCAGAAGATGTCTTTG 123 268 716382 993 100855488 55503 AGCATGGCCTTCCTGG 73 269 716385 1084 1099 79025 79040TTCCCATCCATCAGGA 87 270 716388 1144 1159 79085 79100 AGAGGTGGTCTTGTTC 55271 716391 1206 1221 98908 98923 GGAGCACTCTGACTGA 44 272 716394 13041319 99006 99021 GTTGCTGCAGTCGCAT 120 273 716397 1365 1380 99067 99082GGCCTCACCTGCCGAA 88 274 716400 1423 1438 N/A N/A TAACTCCTGACATTTT 106275 716403 1491 1506 116680 116695 CCGGGAGAAGACACTG 110 276 716406 15761591 120481 120496 ACTCTCATCTCGAGAG 117 277 716409 1636 1651 120541120556 CAGGAAGTCATCTGGG 99 278 716412 1717 1732 122742 122757GTAGTCTGGGAAACGG 41 279 716415 1794 1809 122819 122834 AGCTCCTCTCCTTCTA90 280 716418 1910 1925 122935 122950 CCTGAGGGCTCTATAA 75 281 7164211996 2011 123021 123036 TATTAGCCTGAAAACT 86 282 716424 2064 2079 123089123104 GCAATGGACAAGGAAG 25 283 716427 2170 2185 123195 123210AGCCCCCAAAATGAAC 86 284 716430* 2221 2236 123246 123261 TAACTGGGCAAAAGGA28 285 716433* 2272 2287 123297 123312 AGCATCTGACTTCTAA 20 286 7164362329 2344 123354 123369 ACTGGACAAAGGAAGC 59 287 716439 2387 2402 123412123427 GTATTTAATATCAGAT 77 288 716442 2466 2481 123491 123506GCACTAGGAGGAAAAG 63 289 716445 2559 2574 123584 123599 GTATGTGGCAATAATT28 290 716448 2683 2698 123708 123723 CCGACAAAACCAACCA 62 291 7164512734 2749 123759 123774 CCCAAGCTACAACTAT 67 292 716454 2803 2818 123828123843 CGAGATTTAAATAAGG 27 293 716457 2883 2898 123908 123923AAAGGATACATTCCAC 61 294 716460 2946 2961 123971 123986 TATTCTAAATGCATAC86 295 716463 2998 3013 124023 124038 GACTGCCCCAACCAGA 64 296 7164663071 3086 124096 124111 GTGGAGCACTCCCCTA 58 297 716469 3122 3137 124147124162 GTTTGCTCCTTTCCAA 25 298 716472 3204 3219 124229 124244GTCATGCACATTATGA 78 299 716475 3272 3287 124297 124312 CTTCCAAAACTAAGGC63 300 716478 3330 3345 124355 124370 TATTTTAATCTAGTCG 46 301 7164813382 3397 121835 121850 TCAGCATAGAAGTAGG 23 302 124407 124422 7164843433 3448 124458 124473 CACTTTTCCAGCTAAC 35 303 716487 3541 3556 4291242927 ACACATACTCTAGTTA 64 304 124566 124581 716490 3640 3655 124665124680 ACAACCAACTATTACT 63 305 716493 3692 3707 124717 124732ACATTGAAAGACCCTT 30 306 716496 3745 3760 124770 124785 GAAGAGATTTTATGCC19 307 716499 3852 3867 124877 124892 TTTTGCCCTCCTCCAA 102 308 7165023913 3928 124938 124953 CACAGTGATTGCATTT 11 309 716505 3996 4011 125021125036 GATTTAATCTTTCTGC 35 310 716508 4065 4080 125090 125105CTAGGTAGAATTTCAT 67 311 716511 4131 4146 125156 125171 GATCTTCTGCACATTA51 312 716514 4201 4216 125226 125241 GCTGATATATAAGATA 68 313 7165174255 4270 125280 125295 TTCACAACCCCCCCCC 53 314 716520 4312 4327 125337125352 AGTCTTTATTAAAGAG 96 315 716523 4426 4441 125451 125466CAAATTAAAGTTGAGG 37 316 716526 4481 4496 125506 125521 TCAAAGCACTGTGCCA88 317 716529 4544 4559 125569 125584 CAAACTCAAAAAGGGA 61 318 7165324615 4630 125640 125655 CAAGAAGCAGTTAAGC 70 319 716535 4737 4752 125762125777 CCTGACTGAAAATAAC 86 320 716538 4789 4804 125814 125829TCTGAAACTCCAAATC 77 321 716541 4840 4855 125865 125880 TAAAGGCACTACATTT92 322 716544 4898 4913 125923 125938 TACTTAACACAGCAAC 71 323 7165474986 5001 44309 44324 GGTATGAATTCTGAAT 44 324 126011 126026 716550 50375052 126062 126077 GCACTGAATATTGCCA 77 325 716553 5088 5103 126113126128 ATCCACCTGAGCACTC 54 326 716556 5211 5226 126236 126251GCATTAAAGAATTCTC 39 327 716559 5294 5309 126319 126334 CCTAACATATGAGCAT62 328 716565 N/A N/A 5516 5531 GGGCTAACTACATTGC 129 329 716568 N/A N/A5640 5655 GATTTTTTCTGAGTTC 72 330 716574 N/A N/A 11831 11846TACACTGTATATGTTC 91 331 11769 11784 716577 N/A N/A 58766 58781TCTGTCAGTTATCCTA 21 332 58782 58797

TABLE 5Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 716347 64 79 3524 3539 TGCCTTTCCCCGCCTC 85 333 716350 129 1443589 3604 CTCGGACCTGCGGCGC 99 334 716353 216 231 3676 3691GCATCCCCCGCCCCGG 98 335 716356 296 311 3756 3771 CGAGGTGGAGAAGCGG 112336 716359 348 363 3808 3823 CCCCTGACCCAGGCGA 101 337 716362 433 4483893 3908 AGGCGGCTGCCCTTGG 94 338 716365 533 548 3993 4008TCTGATGCCCGGCGGG 83 339 716368 652 667 4112 4127 GTCGGGCAGCTTCCGG 86 340716371 733 748 7167 7182 TGGAGTCAGGGCTCCT 115 341 716374 802 817 72367251 GGTCAGTGTCCCAGGA 54 342 716377 876 891 7310 7325 GGTATCTCAAAAGAAG76 343 716380 944 959 7378 7393 TTAAGAAGTATCTCTG 54 344 716383 1049 106455544 55559 TCATCATATTCTGCTG 98 345 716386 1110 1125 79051 79066ATTTCTCCATCCTGAG 60 346 716389 1161 1176 79102 79117 AGCCTTGGGTCTAGCC 93347 716392 1266 1281 98968 98983 CTGCCACCCATGACGC 95 348 716395 13311346 99033 99048 GCCGCAGCCTCTCCTT 92 349 716398 1382 1397 N/A N/ATATTCCGCATTGCCTG 70 350 716401 1440 1455 116629 116644 AACTGGCTACGCAGGG92 351 716404 1519 1534 116708 116723 CGTCATTGTTCTCAAT 63 352 7164071593 1608 120498 120513 CTTAGTCCACTGTCTG 35 353 716410 1668 1683 N/A N/AGTATCACCTGTATCCA 52 354 716413 1753 1768 122778 122793 TCCAAGGTCCACATTT79 355 716416 1834 1849 122859 122874 AAGGATGTCAGAACTC 45 356 7164191962 1977 122987 123002 TTTCCGGTGCATGTGT 36 357 716422 2030 2045 123055123070 AGTATCTTGCTGGACG 39 358 716425 2081 2096 123106 123121GCAATACATTAACAGC 71 359 716428* 2187 2202 123212 123227 ACAGGCTCACTTCCCC10 360 716431* 2238 2253 123263 123278 AATGATTGGTGAACAT 55 361 716434*2289 2304 123314 123329 TAAATGCTGTGACATG 44 362 716437 2349 2364 123374123389 CCAGTAAATCATGTTT 41 363 716440 2406 2421 123431 123446CTCTTCAAATCAGCAT 45 364 716443 2483 2498 123508 123523 TTATGTGACTAATGAT73 365 716446 2597 2612 123622 123637 GCACACCCACAAAATT 83 366 7164492700 2715 123725 123740 GGTCATTTGCCTAGGT 49 367 716452 2759 2774 123784123799 TTACCAAAACAACTAC 98 368 716455 2849 2864 123874 123889GTTATGTTTGGGTGTG 17 369 716458 2900 2915 123925 123940 AAGCAGGGAAACCTAA94 370 716461 2963 2978 123988 124003 ATAAACTACTAGTCAT 123 371 7164643015 3030 124040 124055 TACTTCAAACATCTGC 62 372 716467 3088 3103 124113124128 CCGTATGCCCAGAGGG 99 373 716470 3170 3185 124195 124210AATCGAGACTTAAAAA 104 374 716473 3221 3236 124246 124261 CTATAAAGCTTATTTC104 375 716476 3292 3307 124317 124332 GAACTACAAACTAGAA 91 376 7164793348 3363 124373 124388 GAACAATCTTGAAGGC 32 377 716482 3399 3414 124424124439 CTATCCAGGGTCAATT 83 378 716485 3461 3476 124486 124501ACTACCAATATACATT 84 379 716488 3558 3573 38751 38766 CATTATTACTCCTGTA 67380 124583 124598 716491 3658 3673 124683 124698 CTGGTGCCACTTTAAT 54 381716494 3709 3724 124734 124749 AAGGGCTTATTCTAGA 112 382 716497 3762 3777124787 124802 AGCAGCTTTTGCCAGG 65 383 716500 3869 3884 124894 124909AACTTCTTACTTCCAA 18 384 716503 3951 3966 124976 124991 TTATTATGAGTGATCA33 385 716506 4031 4046 125056 125071 TCTGCAGTGGCCATTT 62 386 7165094083 4098 125108 125123 TATACCCAATTTTGCA 70 387 716512 4150 4165 125175125190 ACTCCTTCCAAGTAGC 99 388 716515 4218 4233 125243 125258TAAGCTAAAGCTAATC 123 389 716518 4272 4287 125297 125312 CAAGGTCCCCCTAAAT88 390 716521 4329 4344 125354 125369 CAGCACGGTGTAAGAC 79 391 7165244443 4458 125468 125483 ACTGAGGTATAACTGG 35 392 716527 4502 4517 125527125542 AGTACAGAGGGCATCG 64 393 716530 4561 4576 125586 125601ACATCAAGGCTATGAT 83 394 716533 4666 4681 125691 125706 CAATTCAAGAATACCC64 395 716536 4754 4769 125779 125794 AAGTAGATCTAAGAAG 94 396 7165394806 4821 125831 125846 AATAGTGCTTTGGAAG 59 397 716542 4863 4878 125888125903 CTTCCCTGTGTTCATT 45 398 716545 4916 4931 125941 125956GCATGTATTTAATATG 91 399 716548 5003 5018 126028 126043 GAGTTTCAACACTGAT31 400 716551 5054 5069 126079 126094 CGCTAGAAAAGTGTTA 76 401 7165545105 5120 126130 126145 ATGCTTGCGAGGATAA 30 402 716557 5243 5258 126268126283 ATTGGTACTATATATA 80 403 716560 5312 5327 126337 126352TAACAATTTATGTAAG 107 404 716563 N/A N/A 5445 5460 TGAAGCAAGTTCTCAA 126405 716566 N/A N/A 5552 5567 GGTAACTCTTCTTTCC 102 406 716569 N/A N/A5674 5689 CTCCTTAACCCGGGTT 115 407 716572 N/A N/A 126465 126480CAGTAAGAAGCCAAAA 122 408 716575 N/A N/A 30867 30882 AAAGAACTTAGTTCCC 84409 31189 31204 716578 N/A N/A 70445 70460 AACTTTCACATAAACT 102 41070695 70710

TABLE 6Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 716348 84 99 3544 3559 ACGGAGGCCGGACAGC 107 411 716351 166181 3626 3641 GGTCTGGCGGCTGCGC 112 412 716354 251 266 3711 3726TCGCTCTCAGGGCCGG 114 413 716357 314 329 3774 3789 CGCCCCGGCTCCACGG 127414 716360 388 403 3848 3863 CTGCCCGGGATCCATG 118 415 716363 467 4823927 3942 CGGACGGCGGGCCCTG 103 416 716366 568 583 4028 4043CAGGTCGGTCTCCGAG 95 417 716369 670 685 4130 4145 CGGCGGCTTGAAGAAG 94 418716372 751 766 7185 7200 ATGAGCTCGAACATGC 61 419 716375 819 834 72537268 GAGACTACTCCAGTGG 63 420 716378 893 908 7327 7342 GCAGAGGTACATCATC44 421 716381 961 976 55456 55471 TGTCTGATCGATGTGA 35 422 716384 10661081 N/A N/A AGGACCTGAAGCCGAG 71 423 716387 1127 1142 79068 79083TATGGTTTATATAGTA 33 424 716390 1189 1204 N/A N/A TCTCTGGTTCATGGCA 66 425716393 1285 1300 98987 99002 TTGCTGCTGGTTGGAG 46 426 716396 1348 136399050 99065 CAGTTCTTGCTGTTTC 123 427 716399 1403 1418 102535 102550AATTTGCTGTGCTGGG 40 428 716402 1474 1489 116663 116678 ATTTTGAGTCCCACCA85 429 716405 1547 1562 116736 116751 TGTTAAGGAAAGGATC 149 430 7164081610 1625 120515 120530 CACTGTAGCTGCTCAT 54 431 716411 1700 1715 122725122740 TCTGCTGTGAGGGCAG 102 432 716414 1777 1792 122802 122817GTTCATTCCATCTCCT 59 433 716417 1891 1906 122916 122931 TGTAAGAAAGCTTTCT78 434 716420 1979 1994 24076 24091 CAACTGGCTTATGGAA 50 435 123004123019 716423 2047 2062 71297 71312 GCAAAATAGAGGATTA 43 436 123072123087 716426 2115 2130 123140 123155 TTTGATTCTTTAGAGC 45 437 716429*2204 2219 123229 123244 TGGCATCCATCATCCA 28 438 716432* 2255 2270 123280123295 TCTGAGTATTTAGTTA 30 439 716435* 2306 2321 123331 123346ACAACTGTTGAACAAA 45 440 716438 2366 2381 123391 123406 ATTTTTGGCTTGTCAG32 441 716441 2423 2438 123448 123463 GCCTTGGTTTCAGCTA 57 442 7164442528 2543 123553 123568 AAATTGTCTCATGCCT 40 443 716447 2666 2681 123691123706 CCAACCAACCCCCCCA 97 444 716450 2717 2732 123742 123757AACAGATTCACTAATA 83 445 716453 2786 2801 123811 123826 GGTAAAAAAAACCAGG87 446 716456 2866 2881 123891 123906 ACCACACTATTATAAA 96 447 7164592926 2941 123951 123966 CGCTACCATTTTAAAA 121 448 716462 2981 2996 124006124021 TTAAACTACCAGTGAA 86 449 716465 3036 3051 124061 124076GCTCTTTCTAGAACAC 82 450 716468 3105 3120 124130 124145 TCATCAGATAATATCT118 451 716471 3187 3202 124212 124227 CCTACTCACTGAATTC 48 452 7164743238 3253 124263 124278 TAAATGAAGGTAAACC 120 453 716477 3309 3324 124334124349 GTGTTCATTACAAATG 42 454 716480 3365 3380 124390 124405GCAAGTCTTGTAAGTA 18 455 716483 3416 3431 15582 15597 CAAAACCTTATAGTAT159 456 82739 82754 124441 124456 716486 3494 3509 124519 124534ATCATGATTATCTCTA 68 457 716489 3606 3621 124631 124646 AGTTAATTCATGCTCG23 458 716492 3675 3690 124700 124715 AAACACAGAGGTGCTA 72 459 7164953728 3743 124753 124768 GTTATGAACCCTTGAA 58 460 716498 3833 3848 124858124873 GAAGGGCCAAAATACT 92 461 716501 3891 3906 124916 124931GCACTGAAAGTACTTA 32 462 716504 3970 3985 6107 6122 ATAAAAGCCTTAGAGT 112463 62583 62598 124995 125010 716507 4048 4063 125073 125088ACTACTCTAAAACTCC 53 464 716510 4102 4117 125127 125142 CAACATGCTATGTAAT122 465 716513 4184 4199 125209 125224 AATCTTAATCTGTGGC 30 466 7165164237 4252 125262 125277 AACTTTCCCACCCTCC 84 467 716519 4290 4305 125315125330 GTTTATAAAGTTCTCT 57 468 716522 4363 4378 125388 125403GTGACTGAAACTCTAG 47 469 716525 4460 4475 125485 125500 CACAGTACTGCTACAA64 470 716528 4520 4535 125545 125560 TTAGGTCTCCTTCAGG 70 471 7165314580 4595 125605 125620 GGACATAAAACAAGAG 65 472 716534 4693 4708 125718125733 GATTATAAAATTGGTT 90 473 716537 4772 4787 125797 125812ATGTGCTCCATCAACC 36 474 716540 4823 4838 125848 125863 GAAAAGTTATTACAAC120 475 716543 4880 4895 125905 125920 TATTTGTAGCAAAGTC 35 476 7165464968 4983 125993 126008 CACAATTAATTACTGT 103 477 716549 5020 5035 126045126060 CCACTTTTGCAATGTT 44 478 716552 5071 5086 126096 126111TTTCTCAGATGTACCA 53 479 716555 5167 5182 126192 126207 TACTTTTTCAAGATAC99 480 716558 5277 5292 126302 126317 CTCTTACATCTAAAAC 81 481 7165615338 5353 126363 126378 AAGGTATTACATAAGA 58 482 716564 N/A N/A 5479 5494CTTTTGGGCAAAGTTC 103 483 716567 N/A N/A 5599 5614 GACTATACAACAGGCC 134484 716570 N/A N/A 5717 5732 AAGTGTTTAGGCAAGC 56 485 716573 N/A N/A126516 126531 AGTTACTACTGTAATC 116 486 716576 N/A N/A 58764 58779TGTCAGTTATCCTATC 52 487 58780 58795 716579 N/A N/A 94212 94227ATAGAGATTTTCCCTC 84 488 103505 103520

TABLE 7 Inhibition of Yap1 nRNA by 3-10-3 cEt gapmers targeting SEQ IDNO: 3, and 4 SEQ ID SEQ ID SEQ ID SEQ ID NO: 3 NO: 3 NO: 4 NO: 4 YAP1Compound Start Stop Start Stop (% SEQ ID Number Site Site Site SiteSequence (5′ to 3′) UTC) NO 716562 N/A N/A 1359 1374 GCCTGCCGAAGCAGTT103 489 716571 1062 1077 N/A N/A GCTGAAGCCGAGTTCA 91 490

Example 3 Antisense Inhibition of Human Yap1 in A-431 Cells by cEtGapmers

Modified oligonucleotides were designed to target a Yap1 nucleic acidand were tested for their effect on Yap1 mRNA level in vitro. Themodified oligonucleotides were tested in a series of experiments thathad similar culture conditions. The results for each experiment arepresented in separate tables shown below. Cultured A-431 cells at adensity of 5,000 cells per well were treated using free uptake with2,000 nM of modified oligonucleotide. After a treatment period ofapproximately 48 hours, RNA was isolated from the cells and Yap1 mRNAlevels were measured by quantitative real-time RTPCR. Human primer probeset RTS36584 (forward sequence ACGACCAATAGCTCAGATCCT, designated hereinas SEQ ID NO.: 14; reverse sequence CACCTGTATCCATCTCATCCAC, designatedherein as SEQ ID NO.: 15; probe sequence TGTAGCTGCTCATGCTTAGTCCACTG,designated herein as SEQ ID NO.: 16) was used to measure mRNA levels.Yap1 mRNA levels were normalized to total RNA content, as measured byRIBOGREEN®. Results are presented in the tables below as percent controlof the amount of Yap1 mRNA relative to untreated control cells (% UTC).The modified oligonucleotides with percent control values marked with anasterisk (*) target the amplicon region of the primer probe set.Additional assays may be used to measure the potency and efficacy of themodified oligonucleotides targeting the amplicon region.

The newly designed modified oligonucleotides in the Tables below weredesigned as 3-10-3 cEt gapmers. The gapmers are 16 nucleosides inlength, wherein the central gap segment comprises of ten2′-deoxynucleosides and is flanked by wing segments on the 5′ directionand the 3′ direction comprising three nucleosides each. Each nucleosidein the 5′ wing segment and each nucleoside in the 3′ wing segment has acEt sugar modification. The internucleoside linkages throughout eachgapmer are phosphorothioate (P═S) linkages. All cytosine residuesthroughout each gapmer are 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside to which the gapmer istargeted in the human gene sequence. “Stop site” indicates the 3′-mostnucleoside to which the gapmer is targeted human gene sequence. Eachgapmer listed in the Tables below is targeted to either SEQ ID NO.: 1 orSEQ ID NO.: 2. ‘N/A’ indicates that the modified oligonucleotide doesnot target that particular gene sequence with 100% complementarity.‘N.D.’ indicates that the % UTC is not defined for that particularmodified oligonucleotide in that particular experiment. Activity of themodified oligonucleotide may be defined in a different experiment.

TABLE 8Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 715483 3570 3585 124595 124610 CTCTTTGGAAACCATT 2 206 7154913638 3653 124663 124678 AACCAACTATTACTTC 8 131 958348 556 571 4016 4031CGAGTCCCCGCGGACG 122 491 958349 557 572 4017 4032 CCGAGTCCCCGCGGAC 81492 958350 558 573 4018 4033 TCCGAGTCCCCGCGGA 106 493 958351 560 5754020 4035 TCTCCGAGTCCCCGCG 67 494 958352 563 578 4023 4038CGGTCTCCGAGTCCCC 110 495 958353 564 579 4024 4039 TCGGTCTCCGAGTCCC 43496 958354 565 580 4025 4040 GTCGGTCTCCGAGTCC 31 497 958355 611 626 40714086 CGTTGGCCGTCTTGGG 51 498 958356 663 678 4123 4138 TTGAAGAAGGAGTCGG 9499 958357 667 682 4127 4142 CGGCTTGAAGAAGGAG 12 500 958358 669 684 41294144 GGCGGCTTGAAGAAGG 34 501 958359 709 724 7143 7158 TGCATCAGTACTGGCC117 502 958360 745 760 7179 7194 TCGAACATGCTGTGGA 12 503 958361 747 7627181 7196 GCTCGAACATGCTGTG 8 504 958362 748 763 7182 7197AGCTCGAACATGCTGT 58 505 958363 750 765 7184 7199 TGAGCTCGAACATGCT 70 506958364 969 984 55464 55479 CATGTTGTTGTCTGAT 19 507 958365 971 986 5546655481 GCCATGTTGTTGTCTG 34 508 958366 1607 1622 120512 120527TGTAGCTGCTCATGCT 16* 509 958367 1871 1886 122896 122911 CTAGCTTGGTGGCAGC105 510 958368 1873 1888 122898 122913 ATCTAGCTTGGTGGCA 11 511 9583691875 1890 122900 122915 TTATCTAGCTTGGTGG 4 512 958370 1877 1892 122902122917 CTTTATCTAGCTTGGT 7 513 958371 3637 3652 124662 124677ACCAACTATTACTTCA 2 514 958372 3666 3681 124691 124706 GGTGCTAGCTGGTGCC49 515 958373 3667 3682 124692 124707 AGGTGCTAGCTGGTGC 8 516 958374 36703685 124695 124710 CAGAGGTGCTAGCTGG 38 517 958375 3967 3982 11044 11059AAAGCCTTAGAGTCAA 2 518 124992 125007 958376 1392 1407 102524 102539CTGGGATTGATATTCC 31 519 958377 1393 1408 102525 102540 GCTGGGATTGATATTC9 520 958378 N/A N/A 7141 7156 CATCAGTACTGGCCTA 25 521 958379 N/A N/A3336 3351 GCGCCCGCCCGCACCG 124 522 958380 N/A N/A 3337 3352CGCGCCCGCCCGCACC 106 523 958381 N/A N/A 3344 3359 TCCTCTGCGCGCCCGC 146524 958382 N/A N/A 3345 3360 TTCCTCTGCGCGCCCG 111 525 958383 N/A N/A3346 3361 CTTCCTCTGCGCGCCC 96 526 958384 N/A N/A 3347 3362CCTTCCTCTGCGCGCC 131 527 958385 N/A N/A 4548 4563 GCGCGCGCATTGTGCA 115528 958386 N/A N/A 4549 4564 GGCGCGCGCATTGTGC 111 529 958387 N/A N/A4551 4566 GAGGCGCGCGCATTGT 131 530 958388 N/A N/A 4552 4567GGAGGCGCGCGCATTG 112 531 958389 N/A N/A 4553 4568 CGGAGGCGCGCGCATT 126532 958390 N/A N/A 4571 4586 GCGAAGGTGCGGAGCG 145 533 958391 N/A N/A4572 4587 AGCGAAGGTGCGGAGC 102 534 958392 N/A N/A 5148 5163CTATGAGTCAACCTGC 50 535 958393 N/A N/A 5150 5165 GCCTATGAGTCAACCT 89 536958394 N/A N/A 8647 8662 TTGAAACCTGATCCTT 54 537 958395 N/A N/A 88218836 CTAACAACCTGGTTTG 114 538 958396 N/A N/A 8909 8924 AGGCTATTAAGCTGTT131 539 958397 N/A N/A 8910 8925 CAGGCTATTAAGCTGT 127 540 958398 N/A N/A8911 8926 GCAGGCTATTAAGCTG 76 541 958399 N/A N/A 10927 10942GACCAACTACTTGAAG 45 542 958400 N/A N/A 10929 10944 TTGACCAACTACTTGA 26543 958401 N/A N/A 10964 10979 AGTTATTCAGCAGCTT 19 544 958402 N/A N/A29057 29072 CTCTTACACAGCCTAG 28 545 958403 N/A N/A 36596 36611CAGTTTATGTAGTAGT 5 546 958404 N/A N/A 37602 37617 GCACACAACTCAGACA 52547 958405 N/A N/A 44925 44940 TTATGGGATGAGTGCT 24 548 958406 N/A N/A55773 55788 TTTCAGTTATCGGCCC 29 549 958407 N/A N/A 63319 63334AATACTGATCTGCAGC 35 550 958408 N/A N/A 64348 64363 CTATATATGGTAGTCT 20551 958409 N/A N/A 79120 79135 TTACCAAAACGAGGGT 99 552 958410 N/A N/A79121 79136 TTTACCAAAACGAGGG 70 553 958411 N/A N/A 79122 79137CTTTACCAAAACGAGG 90 554 958412 N/A N/A 79124 79139 ACCTTTACCAAAACGA 49555 958413 N/A N/A 90343 90358 CTAGTAATCTTACTGG 80 556 958414 N/A N/A102402 102417 CAGAATTCCCAAGCTA 73 557 958415 N/A N/A 102449 102464CTGTGTAGGCTGACTT 16 558 958416 N/A N/A 102450 102465 GCTGTGTAGGCTGACT 36559 958417 N/A N/A 102483 102498 ACGGATAAAAATTACT 85 560 958418 N/A N/A102558 102573 AGAGCCTACCTGACAT 47 561 958419 N/A N/A 102560 102575TAAGAGCCTACCTGAC 68 562 958420 N/A N/A 109095 109110 TTCATAATCTGACTAG 66563 958421 N/A N/A 112417 112432 CTCCGTGGTGATCCCA 13 564 958422 N/A N/A115003 115018 TTTCTTAACCAGCGGA 15 565 958423 N/A N/A 121122 121137GATCAACATGCTAACA 51 566

TABLE 9 Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1NO: 2 NO: 2 YAP1 Compound Start Stop Start Stop (% SEQ Number Site SiteSite Site Sequence (5′ to 3′) UTC) ID NO 715483 3570 3585 124595 124610CTCTTTGGAAACCATT 1 206 958436 91 106 3551 3566 TCCCTTGACGGAGGCC 124 567958441 281 296 3741 3756 GCGACGGCTGCGGGCC 72 568 958446 346 361 38063821 CCTGACCCAGGCGAGC 70 569 958451 538 553 3998 4013 CACGATCTGATGCCCG10 570 958456 824 839 7258 7273 GGCCAGAGACTACTCC 90 571 958461 1355 137099057 99072 GCCGAAGCAGTTCTTG 79 572 958466 1840 1855 122865 122880GTCATTAAGGATGTCA 9 573 958471 1943 1958 122968 122983 CTTAGATCCTTCACAG14 574 958476 1961 1976 122986 123001 TTCCGGTGCATGTGTC 2 575 958481 19801995 123005 123020 GCAACTGGCTTATGGA 6 576 958486 2106 2121 123131 123146TTAGAGCCAACTGTGA 9 577 958491 2291 2306 123316 123331 ACTAAATGCTGTGACA 4578 958496 2515 2530 123540 123555 CCTTATAAGCTCCTAA 3 579 958501 26932708 123718 123733 TGCCTAGGTTCCGACA 41 580 958506 2812 2827 123837123852 GCAGATAATCGAGATT 6 581 958511 2870 2885 123895 123910CACTACCACACTATTA 31 582 958516 3003 3018 124028 124043 CTGCAGACTGCCCCAA38 583 958521 3112 3127 124137 124152 TTCCAATTCATCAGAT 14 584 9585263353 3368 124378 124393 AGTAAGAACAATCTTG 6 585 958531 3371 3386 124396124411 GTAGGAGCAAGTCTTG 5 586 958536 3393 3408 124418 124433AGGGTCAATTTTCAGC 3 587 958541 3404 3419 124429 124444 GTATTCTATCCAGGGT 4588 958546 3538 3553 124563 124578 CATACTCTAGTTACAT 6 589 958551 35503565 124575 124590 CTCCTGTAGACACATA 5 590 958556 3639 3654 124664 124679CAACCAACTATTACTT 10 591 958561 3673 3688 124698 124713 ACACAGAGGTGCTAGC48 592 958566 3935 3950 124960 124975 ACCTATGAACTATTAT 18 593 9585714105 4120 125130 125145 CAACAACATGCTATGT 43 594 958576 4173 4188 125198125213 GTGGCTACTGGCAAAT 53 595 958581 4203 4218 125228 125243CTGCTGATATATAAGA 26 596 958586 4331 4346 125356 125371 GGCAGCACGGTGTAAG78 597 958591 4461 4476 125486 125501 TCACAGTACTGCTACA 38 598 9585964610 4625 125635 125650 AGCAGTTAAGCACTTT 3 599 958601 4844 4859 125869125884 CCTTTAAAGGCACTAC 17 600 958606 5087 5102 126112 126127TCCACCTGAGCACTCA 31 601 958611 5284 5299 126309 126324 GAGCATGCTCTTACAT92 602 958616 1141 1156 79082 79097 GGTGGTCTTGTTCTTA 10 603 958621 11721187 79113 79128 AACGAGGGTCAAGCCT 29 604 958626 N/A N/A 5475 5490TGGGCAAAGTTCCTAT 158 605 958631 N/A N/A 5583 5598 TGCAAATAGGAGAGGG 122606 958636 N/A N/A 3328 3343 CCGCACCGCGGCCCGG 126 607 958641 N/A N/A7512 7527 AGCTACAGAGCTTAAC 102 608 958646 N/A N/A 10769 10784TATTATATGGCTAAGC 26 609 958651 N/A N/A 12678 12693 AACTAAAGAGGACTTA 62610 958656 N/A N/A 17870 17885 ACGCAATCTGTGATCC 48 611 958661 N/A N/A21191 21206 TGCCGTTGGCCCCTCC 120 612 958666 N/A N/A 24643 24658GAAAAGGGCAATCATA 52 613 958671 N/A N/A 30409 30424 CATTATATGGCACCCA 19614 958676 N/A N/A 31186 31201 GAACTTAGTTCCCTAT 34 615 958681 N/A N/A34104 34119 AATTAACACCTGAGCT 84 616 958686 N/A N/A 36190 36205CGCAATATAGTCTATA 4 617 958691 N/A N/A 38179 38194 TCAGTTGGCAACAGTC 20618 958696 N/A N/A 40280 40295 GCATACTACACTATAA 56 619 958701 N/A N/A41534 41549 TTAAACTAGGCACATT 98 620 958706 N/A N/A 45392 45407TCGCATGGCCACTGCC 112 621 958711 N/A N/A 48862 48877 CCAAATAAGGATCTGT 34622 958716 N/A N/A 54493 54508 ATGGACTGTATGCAGC 84 623 958721 N/A N/A56973 56988 GTAGTATAATGAGTTA 1 624 105504 105519 958726 N/A N/A 5876558780 CTGTCAGTTATCCTAT 3 625 58781 58796 958731 N/A N/A 58768 58783GCTCTGTCAGTTATCC 7 626 58784 58799 59523 59538 958736 N/A N/A 6219362208 GTGATATGGATTCTGT 3 627 958741 N/A N/A 66072 66087 GTTACTGCAACTGCCC14 628 958746 N/A N/A 70253 70268 GTTATCCTCTATAGTC 22 629 958751 N/A N/A75535 75550 TCAATGCAGGATTCCA 30 630 958756 N/A N/A 79463 79478GTGTTGCATGACAGCC 15 631 958761 N/A N/A 82824 82839 AGTCTCAACAACCTTC 7632 958766 N/A N/A 86559 86574 TAACATATGTCTACTC 23 633 958771 N/A N/A92071 92086 CTACAGACGAATTCCA 18 634 958776 N/A N/A 94770 94785GGTACTCTCCTTCAGA 94 635 958781 N/A N/A 97391 97406 GTCATCTATGTGTCCT 6636 958786 N/A N/A 99922 99937 TATGTCCTACTTTCCC 10 637 958791 N/A N/A102044 102059 CATAAGAAAAGACGAC 123 638 958796 N/A N/A 103309 103324ATTATATGGTTGCTTC 3 639 958801 N/A N/A 108999 109014 CGCTAGCACGCGCGCT 131640 958806 N/A N/A 112159 112174 TGCCTAGGGTTCTGTG 30 641 958811 N/A N/A115185 115200 CACTGAGGCACGGCCC 92 642 958816 N/A N/A 120622 120637GTGATAACATATCCCA 71 643

TABLE 10Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 715483 3570 3585 124595 124610 CTCTTTGGAAACCATT 2 206 958437134 149 3594 3609 AGGCACTCGGACCTGC 84 644 958442 290 305 3750 3765GGAGAAGCGGCGACGG 21 645 958447 404 419 3864 3879 GTTGAGGCGGCGGCTG 48 646958452 571 586 4031 4046 CTCCAGGTCGGTCTCC 26 647 958457 857 872 72917306 GTCGAAGATGCTGAGC 5 648 958462 1439 1454 116628 116643ACTGGCTACGCAGGGC 46 649 958467 1864 1879 122889 122904 GGTGGCAGCCAAAACA32 650 958472 1945 1960 122970 122985 TCCTTAGATCCTTCAC 5 651 958477 19631978 122988 123003 ATTTCCGGTGCATGTG 2 652 958482 2000 2015 123025 123040TCTGTATTAGCCTGAA 10 653 958487 2192 2207 123217 123232 TCCAAACAGGCTCACT10 654 958492 2356 2371 123381 123396 TGTCAGACCAGTAAAT 12 655 9584972534 2549 123559 123574 ATATGGAAATTGTCTC 1 656 958502 2722 2737 123747123762 CTATTAACAGATTCAC 13 657 958507 2814 2829 123839 123854GAGCAGATAATCGAGA 6 658 958512 2875 2890 123900 123915 CATTCCACTACCACAC14 659 958517 3030 3045 124055 124070 TCTAGAACACTAAACT 88 660 9585223156 3171 124181 124196 AATTAGTCCAAGGGAG 32 661 958527 3356 3371 124381124396 GTAAGTAAGAACAATC 4 662 958532 3374 3389 124399 124414GAAGTAGGAGCAAGTC 2 663 958537 3394 3409 124419 124434 CAGGGTCAATTTTCAG 3664 79237 79252 958542 3408 3423 124433 124448 TATAGTATTCTATCCA 4 66596503 96518 102951 102966 958547 3540 3555 124565 124580CACATACTCTAGTTAC 4 666 56579 56594 958552 3555 3570 124580 124595TATTACTCCTGTAGAC 16 667 958557 3641 3656 124666 124681 CACAACCAACTATTAC10 668 958562 3691 3706 124716 124731 CATTGAAAGACCCTTA 6 669 958567 39383953 124963 124978 TCAACCTATGAACTAT 3 670 958572 4159 4174 125184 125199ATTATAGGCACTCCTT 5 671 958577 4176 4191 125201 125216 TCTGTGGCTACTGGCA 4672 958582 4206 4221 125231 125246 AATCTGCTGATATATA 21 673 958587 43644379 125389 125404 GGTGACTGAAACTCTA 2 674 958592 4488 4503 125513 125528CGTAAGATCAAAGCAC 12 675 958597 4626 4641 125651 125666 CCCAATACAACCAAGA6 676 958602 4936 4951 125961 125976 TGCCATGTTCCATATA 16 677 958607 51095124 126134 126149 CAACATGCTTGCGAGG 11 678 958612 5295 5310 126320126335 ACCTAACATATGAGCA 18 679 958617 1143 1158 79084 79099GAGGTGGTCTTGTTCT 40 680 958622 1384 1399 102516 102531 GATATTCCGCATTGCC3 681 958627 N/A N/A 5476 5491 TTGGGCAAAGTTCCTA 61 682 958632 N/A N/A5610 5625 CTCCGACAGGAGACTA 55 683 958637 N/A N/A 4394 4409CCGCAGAGAGAAACTC 101 684 958642 N/A N/A 8249 8264 GACATCAATTTCAGTC 91685 958647 N/A N/A 10939 10954 TAGGAAGTTGTTGACC 11 686 958652 N/A N/A14156 14171 GCTACGACGGCTGGCC 136 687 958657 N/A N/A 18786 18801CAGTATAATATCCTAA 37 688 958662 N/A N/A 21800 21815 GAACAGATAGGACTAC 51689 958667 N/A N/A 25870 25885 TGCCGGGCCCCTATGC 80 690 958672 N/A N/A30864 30879 GAACTTAGTTCCCTTC 67 691 958677 N/A N/A 31187 31202AGAACTTAGTTCCCTA 51 692 958682 N/A N/A 34164 34179 CCATGAGGGACTCCCA 123693 958687 N/A N/A 36660 36675 ACACTATGTGTTCTGC 57 694 958692 N/A N/A39314 39329 GGCTAGAGGCCGGGTG 105 695 958697 N/A N/A 40306 40321CTAAAGATGACTACTG 39 696 958702 N/A N/A 41672 41687 TGATGTCTTGTCCAGA 16697 958707 N/A N/A 46503 46518 TCAATGCTGTATCAGA 23 698 958712 N/A N/A49103 49118 TTATATAGGTTACAGA 52 699 958717 N/A N/A 55730 55745AATAATATAGCTTACG 11 700 958722 N/A N/A 57612 57627 CATAATAGGACACAAC 59701 958727 N/A N/A 58767 58782 ATCTGTCAGTTATCCT 2 702 958732 N/A N/A59675 59690 AGCACGGTGTAGCTTT 60 703 958737 N/A N/A 62586 62601GGAATACAAGCCCGAG 8 704 958742 N/A N/A 66232 66247 AGCAATATGGTATTAG 4 705958747 N/A N/A 72144 72159 GTAAAGAGGGTGACAT 106 706 958752 N/A N/A 7558275597 GAATTTTTAGTCCAGT 2 707 958757 N/A N/A 79978 79993 GTGATCTGCACATTGT5 708 958762 N/A N/A 84225 84240 GATTAGAGGACTCATT 16 709 958767 N/A N/A86751 86766 ACGAATAAGGCATTAG 6 710 958772 N/A N/A 92334 92349CAACAAACATAGTTAC 61 711 958777 N/A N/A 94786 94801 GTAACTGTTTCTAGGT 10712 958782 N/A N/A 97670 97685 ATGGTCTCCCAGTCAC 20 713 958787 N/A N/A101109 101124 TGGGCAAAGTTCCTCT 67 714 958792 N/A N/A 102355 102370GCCAATGGAGTCACCA 46 715 958797 N/A N/A 105351 105366 ACGAGCACAGCACCCT 13716 958802 N/A N/A 110683 110698 AGATAATCATCCTCAA 25 717 958807 N/A N/A112517 112532 TCATTGTAGTCTGTCT 3 718 958812 N/A N/A 115821 115836TACTATAAGACACCAA 31 719 958817 N/A N/A 121734 121749 TGCCAGGTAAGCCACA 30720

TABLE 11Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 715483 3570 3585 124595 124610 CTCTTTGGAAACCATT 1 206 958438181 196 3641 3656 CGCCCCGGCTCCACTG 61 721 958443 306 321 3766 3781CTCCACGGGCCGAGGT 90 722 958448 437 452 3897 3912 GCGAAGGCGGCTGCCC 86 723958453 635 650 4095 4110 GCCTCATGGGCACGGT 70 724 958458 1006 1021 5550155516 GTTCATCTGGGACAGC 12 725 958463 1502 1517 116691 116706CCTGAGACATCCCGGG 63 726 958468 1866 1881 122891 122906 TTGGTGGCAGCCAAAA86 727 958473 1948 1963 122973 122988 GTCTCCTTAGATCCTT 5 728 958478 19671982 122992 123007 GGAAATTTCCGGTGCA 14 729 958483 2039 2054 123064123079 GAGGATTAAAGTATCT 17 730 958488 2209 2224 123234 123249AGGAATGGCATCCATC 41 731 958493 2435 2450 123460 123475 AAACAGTCTTCAGCCT16 732 958498 2561 2576 74512 74527 GAGTATGTGGCAATAA 1 733 123586 123601958503 2740 2755 123765 123780 AACCATCCCAAGCTAC 15 734 958508 2816 2831123841 123856 GAGAGCAGATAATCGA 7 735 958513 2927 2942 123952 123967GCGCTACCATTTTAAA 104 736 958518 3047 3062 124072 124087 CCACAGTAATAGCTCT1 737 958523 3174 3189 124199 124214 TTCCAATCGAGACTTA 3 738 958528 33623377 124387 124402 AGTCTTGTAAGTAAGA 18 739 958533 3379 3394 124404124419 GCATAGAAGTAGGAGC 3 740 958538 3397 3412 31598 31613ATCCAGGGTCAATTTT 10 741 124422 124437 958543 3412 3427 124437 124452ACCTTATAGTATTCTA 4 742 958548 3542 3557 124567 124582 GACACATACTCTAGTT21 743 958553 3559 3574 38752 38767 CCATTATTACTCCTGT 1 744 121706 121721124584 124599 958558 3643 3658 124668 124683 TTCACAACCAACTATT 9 745958563 3759 3774 124784 124799 AGCTTTTGCCAGGAGA 3 746 958568 3947 3962124972 124987 TATGAGTGATCAACCT 5 747 958573 4164 4179 125189 125204GGCAAATTATAGGCAC 2 748 958578 4181 4196 125206 125221 CTTAATCTGTGGCTAC 4749 958583 4210 4225 125235 125250 AGCTAATCTGCTGATA 89 750 958588 43734388 125398 125413 GTGTACTTAGGTGACT 10 751 958593 4506 4521 125531125546 GGTCAGTACAGAGGGC 7 752 958598 4636 4651 125661 125676CCCAATGCTACCCAAT 4 753 958603 4987 5002 44310 44325 TGGTATGAATTCTGAA 3754 75463 75478 126012 126027 958608 5136 5151 126161 126176TGATAGGCACACCCAC 11 755 958613 1062 1077 55557 55572 CCTGAAGCCGAGTTCA 15756 958618 1149 1164 79090 79105 AGCCAAGAGGTGGTCT 36 757 958623 13861401 102518 102533 TTGATATTCCGCATTG 3 758 958628 N/A N/A 5514 5529GCTAACTACATTGCAG 81 759 958633 N/A N/A 5656 5671 TGTCATCAGGTTAAGT 76 760958638 N/A N/A 4565 4580 GTGCGGAGCGCGCGGA 127 761 958643 N/A N/A 84578472 TAGCAACCCACCCTGG 59 762 958648 N/A N/A 10980 10995 GAATACTGAGTCAGGA7 763 958653 N/A N/A 15503 15518 TTACACACAGGCTATG 17 764 958658 N/A N/A18787 18802 ACAGTATAATATCCTA 6 765 958663 N/A N/A 22200 22215CTATTAGGGACTGAAC 32 766 958668 N/A N/A 27649 27664 GTGATCTGTGAGAGGT 2767 958673 N/A N/A 30865 30880 AGAACTTAGTTCCCTT 30 768 958678 N/A N/A32244 32259 GGAGGAGTCACCATGG 74 769 958683 N/A N/A 34256 34271TATTGTGCTGCATCTC 16 770 958688 N/A N/A 36686 36701 GGCTATGTAGCCTTCC 82771 958693 N/A N/A 39371 39386 GTGGTGTCTCACAGGC 99 772 958698 N/A N/A40400 40415 CTTATTAGCCCTCAAA 30 773 958703 N/A N/A 43429 43444GATAACTAAGCACTAC 49 774 958708 N/A N/A 46790 46805 ATGTCAGATGTCAATT 19775 958713 N/A N/A 50391 50406 TGCTAGAGGCTGTTCC 55 776 958718 N/A N/A55941 55956 GAACACTATAGCTTGG 4 777 958723 N/A N/A 58021 58036AACCCACTAAAACCGG 63 778 958728 N/A N/A 45026 45041 TATCTGTCAGTTATCC 10779 58768 58783 58784 58799 958733 N/A N/A 60397 60412 TAATAGACTAGACTTA67 780 958738 N/A N/A 63528 63543 TCTATATGTTTCCCCC 11 781 958743 N/A N/A66740 66755 GACTATAAAGGGTTTA 30 782 958748 N/A N/A 72564 72579ACATGTGACATTCCGG 83 783 958753 N/A N/A 76248 76263 TGTATATGCCGTTCCC 4784 958758 N/A N/A 79985 80000 CTATTCAGTGATCTGC 2 785 958763 N/A N/A84603 84618 CACAATACAAGATGCA 3 786 958768 N/A N/A 87653 87668GTGCAAGCAGGTTCCC 17 787 958773 N/A N/A 93005 93020 AGCTGGTAGGGCAAGA 43788 958778 N/A N/A 95129 95144 GCTACCTGGAGCGAAG 75 789 958783 N/A N/A98257 98272 TGATCTGATGCTTGCT 35 790 958788 N/A N/A 101110 101125CTGGGCAAAGTTCCTC 54 791 958793 N/A N/A 102510 102525 CCGCATTGCCTAAGAG 9792 958798 N/A N/A 107371 107386 TGCAGTATAATATCCT 3 793 958803 N/A N/A110998 111013 GATAATCATCCTCAGC 24 794 958808 N/A N/A 113126 113141AGCGATTGGCCTCCCA 59 795 958813 N/A N/A 116872 116887 TTACAGAGAGATTCAT 8796 958818 N/A N/A 121757 121772 GTTGTCAACTCTAGGG 23 797

TABLE 12Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 715483 3570 3585 124595 124610 CTCTTTGGAAACCATT 1 206 958439182 197 3642 3657 GCGCCCCGGCTCCACT 77 798 958444 315 330 3775 3790ACGCCCCGGCTCCACG 97 799 958449 468 483 3928 3943 CCGGACGGCGGGCCCT 84 800958454 754 769 7188 7203 GGAATGAGCTCGAACA 3 801 958459 1061 1076 5555655571 CTGAAGCCGAGTTCAT 28 802 958464 1600 1615 120505 120520GCTCATGCTTAGTCCA 3* 803 958469 1904 1919 122929 122944 GGCTCTATAACCATGT17 804 958474 1950 1965 122975 122990 GTGTCTCCTTAGATCC 3 805 958479 19691984 122994 123009 ATGGAAATTTCCGGTG 15 806 958484 2067 2082 123092123107 GCAGCAATGGACAAGG 2 807 958489 2262 2277 123287 123302TTCTAAGTCTGAGTAT 14 808 958494 2468 2483 123493 123508 TAGCACTAGGAGGAAA28 809 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 958504 28052820 123830 123845 ATCGAGATTTAAATAA 63 811 958509 2851 2866 123876123891 ATGTTATGTTTGGGTG 4 812 958514 2957 2972 123982 123997TACTAGTCATGTATTC 20 813 958519 3061 3076 124086 124101 CCCCTAGGCACTATCC20 814 958524 3199 3214 124224 124239 GCACATTATGAACCTA 13 815 9585293364 3379 124389 124404 CAAGTCTTGTAAGTAA 3 816 958534 3383 3398 121836121851 TTCAGCATAGAAGTAG 3 817 124408 124423 958539 3400 3415 124425124440 TCTATCCAGGGTCAAT 11 818 958544 3471 3486 124496 124511GCTAAATTCAACTACC 8 819 958549 3546 3561 100828 100843 TGTAGACACATACTCT 8820 110388 110403 124571 124586 958554 3561 3576 38754 38769AACCATTATTACTCCT 1 821 120229 120244 124586 124601 958559 3645 3660124670 124685 AATTCACAACCAACTA 17 822 958564 3841 3856 124866 124881TCCAAATTGAAGGGCC 62 823 958569 3965 3980 124990 125005 AGCCTTAGAGTCAATT3 824 958574 4166 4181 125191 125206 CTGGCAAATTATAGGC 13 825 958579 41834198 125208 125223 ATCTTAATCTGTGGCT 4 826 958584 4221 4236 125246 125261CCCTAAGCTAAAGCTA 74 827 958589 4409 4424 125434 125449 GTAAAGGAAGATCTCC4 828 958594 4523 4538 125548 125563 CTCTTAGGTCTCCTTC 8 829 958599 46634678 125688 125703 TTCAAGAATACCCAGT 5 830 958604 5055 5070 126080 126095ACGCTAGAAAAGTGTT 94 831 958609 5221 5236 126246 126261 TGACAAGTGTGCATTA16 832 958614 1137 1152 79078 79093 GTCTTGTTCTTATGGT 6 833 958619 11561171 79097 79112 TGGGTCTAGCCAAGAG 71 834 958624 1390 1405 102522 102537GGGATTGATATTCCGC 74 835 958629 N/A N/A 5523 5538 CCCGAGTGGGCTAACT 128836 958634 N/A N/A 5673 5688 TCCTTAACCCGGGTTT 61 837 958639 N/A N/A 67836798 GTTATGGGTGCTTTTC 18 838 958644 N/A N/A 8524 8539 ATGATCAAACCTTTTC 5839 958649 N/A N/A 12237 12252 TGCCACTGGTGAATAC 36 840 958654 N/A N/A16919 16934 AATGGAGTGGCCGGGC 110 841 958659 N/A N/A 18852 18867GTTGTATTACTCTCCA 2 842 958664 N/A N/A 23239 23254 ACGAACTAAGGTGTAC 40843 958669 N/A N/A 28420 28435 GCTATCTTTGGATCCA 76 844 958674 N/A N/A30866 30881 AAGAACTTAGTTCCCT 25 845 31188 31203 958679 N/A N/A 3391733932 GTAACTGCCACAGTTA 77 846 958684 N/A N/A 35513 35528GCTGAAGACGGCCCTT 70 847 958689 N/A N/A 36864 36879 CATTAAGGAGGTTATG 87848 958694 N/A N/A 39375 39390 ATTGGTGGTGTCTCAC 41 849 958699 N/A N/A40415 40430 GACTAGAAAGATCATC 20 850 958704 N/A N/A 43572 43587CCCTACACTCGAGGAT 122 851 958709 N/A N/A 46944 46959 TCAATCTATGAGACCC 57852 958714 N/A N/A 52275 52290 GAGCACTGCGCCCTGG 82 853 958719 N/A N/A56409 56424 GTACATAATGGGCTAA 49 854 958724 N/A N/A 58762 58777TCAGTTATCCTATCCC 2 855 958729 N/A N/A 58763 58778 GTCAGTTATCCTATCT 4 85658779 58794 958734 N/A N/A 61207 61222 ACACATAGAGCTAAGG 7 857 958739 N/AN/A 64256 64271 AGCAATAGAGTAACCA 4 858 958744 N/A N/A 67858 67873GCATACTGGTGCCCCA 45 859 958749 N/A N/A 74623 74638 CCACAAGGGCAGTACG 51860 958754 N/A N/A 77489 77504 CCTTAGGAAGGCTCCC 31 861 958759 N/A N/A81664 81679 GCCTATCGCCCCAAGC 61 862 958764 N/A N/A 85543 85558TGGGTCTCTTGATTTC 34 863 958769 N/A N/A 89667 89682 CATTGCCACGATCTAA 36864 958774 N/A N/A 94013 94028 TGCTAGATATCGCCAA 33 865 958779 N/A N/A95898 95913 TCGAATATAGAGGCCT 80 866 958784 N/A N/A 99202 99217GGCTGGATAGAATGCT 79 867 958789 N/A N/A 101277 101292 TACTATATAATACCCT 17868 958794 N/A N/A 102512 102527 TTCCGCATTGCCTAAG 14 869 958799 N/A N/A107814 107829 ATTACTCAATCATGGT 2 870 958804 N/A N/A 110999 111014AGATAATCATCCTCAG 17 871 958809 N/A N/A 113144 113159 TCTTAACACCTGAGCT 66872 958814 N/A N/A 117837 117852 GGCTATGCCTCTCTTA 214 873 958819 N/A N/A122502 122517 TGCTTCAACATTGTTC 9 874

TABLE 13Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 715483 3570 3585 124595 124610 CTCTTTGGAAACCATT 1 206 958440183 198 3643 3658 TGCGCCCCGGCTCCAC 54 875 958445 327 342 3787 3802GGCTACGCCCGGACGC 63 876 958450 496 511 3956 3971 GGTCGCCGCGGGTGCC 59 877958455 757 772 7191 7206 AGAGGAATGAGCTCGA 43 878 958460 1294 1309 9899699011 TCGCATCTGTTGCTGC 52 879 958465 1726 1741 122751 122766GGCTTCAAGGTAGTCT 84 880 958470 1941 1956 8781 8796 TAGATCCTTCACAGAT 18881 45134 45149 122966 122981 958475 1959 1974 122984 122999CCGGTGCATGTGTCTC 37 882 958480 1978 1993 24075 24090 AACTGGCTTATGGAAA 24883 123003 123018 958485 2089 2104 56507 56522 AGAGGTCAGCAATACA 3 884122015 122030 123114 123129 958490 2281 2296 123306 123321GTGACATGAAGCATCT 5 885 958495 2488 2503 123513 123528 GGTCATTATGTGACTA56 886 958500 2570 2585 123595 123610 TCTATATTAGAGTATG 5 887 958505 28092824 123834 123849 GATAATCGAGATTTAA 6 888 958510 2867 2882 123892 123907TACCACACTATTATAA 43 889 958515 2993 3008 124018 124033 CCCCAACCAGATTTAA28 890 958520 3091 3106 124116 124131 CTACCGTATGCCCAGA 27 891 9585253235 3250 124260 124275 ATGAAGGTAAACCACT 3 892 958530 3367 3382 124392124407 GAGCAAGTCTTGTAAG 20 893 958535 3392 3407 124417 124432GGGTCAATTTTCAGCA 10 894 958540 3402 3417 124427 124442 ATTCTATCCAGGGTCA8 895 958545 3535 3550 5536 5551 ACTCTAGTTACATCAT 3 896 124560 124575958550 3548 3563 124573 124588 CCTGTAGACACATACT 4 897 958555 3619 3634124644 124659 GCTTATATTGAAGAGT 4 898 958560 3656 3671 124681 124696GGTGCCACTTTAATTC 22 899 958565 3895 3910 124920 124935 TTGAGCACTGAAAGTA4 900 958570 4092 4107 125117 125132 TGTAATTCATATACCC 5 901 958575 41714186 125196 125211 GGCTACTGGCAAATTA 9 902 958580 4186 4201 125211 125226ATAATCTTAATCTGTG 4 903 958585 4278 4293 125303 125318 CTCTATCAAGGTCCCC 5904 958590 4439 4454 125464 125479 AGGTATAACTGGGCAA 2 905 958595 45634578 125588 125603 CCACATCAAGGCTATG 8 906 958600 4752 4767 125777 125792GTAGATCTAAGAAGCC 8 907 958605 5068 5083 126093 126108 CTCAGATGTACCAACG 7908 958610 5250 5265 126275 126290 AGGTAACATTGGTACT 34 909 958615 11391154 79080 79095 TGGTCTTGTTCTTATG 3 910 958620 1162 1177 79103 79118AAGCCTTGGGTCTAGC 57 911 958625 1394 1409 102526 102541 TGCTGGGATTGATATT6 912 958630 N/A N/A 5554 5569 GCGGTAACTCTTCTTT 52 913 958635 N/A N/A5713 5728 GTTTAGGCAAGCAGCT 43 914 958640 N/A N/A 7413 7428TAGATAACTGTCTCCC 13 915 958645 N/A N/A 9559 9574 GCCCATAGTTGACAGG 54 916958650 N/A N/A 12498 12513 TCAATTGAGTCTGCTA 3 917 958655 N/A N/A 1786817883 GCAATCTGTGATCCCA 12 918 958660 N/A N/A 19378 19393CCCACTGGGTTTGTCC 106 919 958665 N/A N/A 23878 23893 CTGCATACCCTCCAGC 84920 958670 N/A N/A 28665 28680 GGTCTTGGTGATTGGC 20 921 958675 N/A N/A31177 31192 TCCCTATCAGCTGGGC 112 922 958680 N/A N/A 34103 34118ATTAACACCTGAGCTG 50 923 958685 N/A N/A 35577 35592 AGCTATGGAAAGTGTC 24924 958690 N/A N/A 37103 37118 TGGACTCTTGATCACA 26 925 958695 N/A N/A39759 39774 TCAATTCTCCACCAGA 45 926 958700 N/A N/A 41085 41100CTAATATAGACTACTC 55 927 958705 N/A N/A 45162 45177 GGCCATCAATAAAGAC 112928 958710 N/A N/A 47735 47750 AGGGAACCCTTGGCTA 77 929 958715 N/A N/A53767 53782 GTAATAGGAGGTAAGA 48 930 958720 N/A N/A 56594 56609GTCTACTAGAGCTGCC 12 931 958725 N/A N/A 58763 58778 GTCAGTTATCCTATCC 1932 958730 N/A N/A 58783 58798 CTCTGTCAGTTATCCT 4 933 958735 N/A N/A61265 61280 AGCAATCTTGTGGATC 7 934 958740 N/A N/A 65047 65062CGGCACCAAACACCCA 57 935 958745 N/A N/A 69906 69921 TCCCAGCCGCATGGCT 78936 958750 N/A N/A 75333 75348 TGTAAGAGGAGACCAC 28 937 958755 N/A N/A78709 78724 TAACATAAGACACGGA 12 938 958760 N/A N/A 82249 82264AGTAATAGATCTACAA 76 939 958765 N/A N/A 86532 86547 GTACAGGAGAGATTGC 37940 958770 N/A N/A 90915 90930 ACAGAGCGGTGCACCC 64 941 958775 N/A N/A94061 94076 GTCTATACGGGAGATT 29 942 958780 N/A N/A 96542 96557TCAACTACTTTTCAGC 24 943 958785 N/A N/A 99371 99386 GCAATCCACAATTCCA 2944 958790 N/A N/A 102039 102054 GAAAAGACGACACAGT 68 945 958795 N/A N/A102514 102529 TATTCCGCATTGCCTA 8 946 958800 N/A N/A 108359 108374TCGATAATATATGGCA 22 947 958805 N/A N/A 111001 111016 CAAGATAATCATCCTC 6948 958810 N/A N/A 114182 114197 TTATATACGGGAAAAT 47 949 958815 N/A N/A120003 120018 GGGCGAGGAGACAGGT 16 950 958820 N/A N/A 126468 126483GACCAGTAAGAAGCCA 49 951

Example 4 Antisense Inhibition of Human Yap1 in A-431 Cells by cEtGapmers

Modified oligonucleotides were designed to target a Yap1 nucleic acidand were tested for their effect on Yap1 mRNA level in vitro. Themodified oligonucleotides were tested in a series of experiments thathad similar culture conditions. The results for each experiment arepresented in separate tables shown below. Cultured A-431 cells at adensity of 5,000 cells per well were treated using free uptake with2,000 nM of modified oligonucleotide. After a treatment period ofapproximately 48 hours, RNA was isolated from the cells and Yap1 mRNAlevels were measured by quantitative real-time RTPCR. Human primer probeset RTS4814 was used to measure mRNA levels. Yap1 mRNA levels werenormalized to total RNA content, as measured by RIBOGREEN®. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC). The modifiedoligonucleotides with percent control values marked with an asterisk (*)target the amplicon region of the primer probe set. Additional assaysmay be used to measure the potency and efficacy of the modifiedoligonucleotides targeting the amplicon region.

The newly designed modified oligonucleotides in the Tables below weredesigned as 3-10-3 cEt gapmers. The gapmers are 16 nucleosides inlength, wherein the central gap segment comprises of ten2′-deoxynucleosides and is flanked by wing segments on the 5′ directionand the 3′ direction comprising three nucleosides each. Each nucleosidein the 5′ wing segment and each nucleoside in the 3′ wing segment has acEt sugar modification. The internucleoside linkages throughout eachgapmer are phosphorothioate (P═S) linkages. All cytosine residuesthroughout each gapmer are 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside to which the gapmer istargeted in the human gene sequence. “Stop site” indicates the 3′-mostnucleoside to which the gapmer is targeted human gene sequence. Eachgapmer listed in the Tables below is targeted to either SEQ ID NO.: 1,SEQ ID NO.: 2, SEQ ID NO.: 3 (GENBANK Accession No. NM_006106.4), or SEQID NO.: 4 (GENBANK Accession No. NM_001130145.2). ‘N/A’ indicates thatthe modified oligonucleotide does not target that particular genesequence with 100% complementarity. ‘N.D.’ indicates that the % UTC isnot defined for that particular modified oligonucleotide in thatparticular experiment. Activity of the modified oligonucleotide may bedefined in a different experiment.

TABLE 14Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 107411297 112 3557 3572 TCCAACTCCCTTGACG 83 952 1074144 285 300 3745 3760AGCGGCGACGGCTGCG 92 953 1074176 364 379 3824 3839 CTCCCCCGACGCGCAC 84954 1074208 541 556 4001 4016 GTGCACGATCTGATGC 96 955 1074240 896 9117330 7345 CTGGCAGAGGTACATC 29 956 1074272 1118 1133 79059 79074TATAGTAAATTTCTCC 16 957 1074304 1357 1372 99059 99074 CTGCCGAAGCAGTTCT109 958 1074336 1451 1466 116640 116655 CCAGTGTTGGTAACTG 97 959 10743681672 1687 N/A N/A GATAGTATCACCTGTA 8 960 1074400 1928 1943 122953 122968GATTTAGAATTCAGTC 42 961 1074432 2243 2258 123268 123283 GTTAAAATGATTGGTG3* 962 1074464 2564 2579 123589 123604 TTAGAGTATGTGGCAA 2 963 10744962743 2758 123768 123783 AATAACCATCCCAAGC 69 964 1074528 2996 3011 124021124036 CTGCCCCAACCAGATT 25 965 1074560 3172 3187 124197 124212CCAATCGAGACTTAAA 3 966 1074592 3368 3383 124393 124408 GGAGCAAGTCTTGTAA23 967 1074624 3706 3721 124731 124746 GGCTTATTCTAGAAAC 65 968 10746564008 4023 125033 125048 GACTTAATTCAAGATT 31 969 1074688 4224 4239 125249125264 TCCCCCTAAGCTAAAG 83 970 1074720 4403 4418 125428 125443GAAGATCTCCATATTC 58 971 1074752 4592 4607 125617 125632 CATTAGGAACAAGGAC10 972 1074784 4758 4773 125783 125798 CCATAAGTAGATCTAA 25 973 10748165032 5047 126057 126072 GAATATTGCCACCCAC 15 974 1074848 5140 5155 126165126180 GTTATGATAGGCACAC 11 975 1074912 N/A N/A 5525 5540ATCCCGAGTGGGCTAA 85 976 1074944 N/A N/A 5623 5638 AAAACCCTTTGGTCTC 89977 1074976 N/A N/A 126479 126494 TTCTATTGGAAGACCA 35 978 1075008 N/AN/A 5286 5301 TAATCGAACATTGTGT 61 979 1075040 N/A N/A 7618 7633TTATAAAGAGGCTCAG 10 980 1075072 N/A N/A 9650 9665 TCCGGGTAAATATCTC 37981 1075104 N/A N/A 11109 11124 ATTATAAGGTCCTACA 67 982 1075136 N/A N/A13294 13309 CTAGAATATTAAAGGG 87 983 1075168 N/A N/A 16596 16611CATCAAAATTTCACGA 49 984 1075200 N/A N/A 21836 21851 CATATTAACTAGATGA 120985 1075232 N/A N/A 24676 24691 ATTTATCAGCCATTGT 13 986 1075264 N/A N/A27401 27416 GAATAATATGCAGAAC 53 987 1075296 N/A N/A 30827 30842ATTATAAGCTGTGTTG 18 988 1075328 N/A N/A 32291 32306 CTCGCAAAGCCTCTTC 21989 1075360 N/A N/A 34021 34036 AGGCAACAACATCTAA 50 990 1075392 N/A N/A36045 36060 GACGGGTGAACCTGTT 95 991 1075424 N/A N/A 38749 38764TTATTAATCCTGTCCA 18 992 1075456 N/A N/A 40812 40827 TTACGAAATGTTTAGT 61993 1075488 N/A N/A 42808 42823 CAGAATAAGGGAGATC 56 994 1075520 N/A N/A45363 45378 CCCCAACAACTGCTAA 77 995 1075552 N/A N/A 47526 47541GATTATAACATGCTGT 74 996 1075584 N/A N/A 49326 49341 AATAATTGACCTAGCA 57997 1075616 N/A N/A 51128 51143 GTAAAACCGATTTTTC 46 998 1075648 N/A N/A52713 52728 TCAATAAAGTGGGACT 67 999 1075680 N/A N/A 55168 55183ATTATTACCCCTTCTA 73 1000 1075712 N/A N/A 57557 57572 GACGCGAAATACTTAC 71001 1075744 N/A N/A 59642 59657 TTCGGGTTAGCAGACT 6 1002 1075776 N/A N/A62195 62210 ATGTGATATGGATTCT 10 1003 1075808 N/A N/A 64255 64270GCAATAGAGTAACCAG 3 1004 1075840 N/A N/A 67174 67189 CCTAAAATAGGAATGC 891005 1075872 N/A N/A 70920 70935 CAATTATGACAAACAG 21 1006 1075904 N/AN/A 73288 73303 GTATAGGATCTACTAA 51 1007 1075936 N/A N/A 76577 76592CTTATATTCTCTCCGA 49 1008 1075968 N/A N/A 80319 80334 TATTTAAGCCAAACCG 51009 1076000 N/A N/A 82082 82097 CCTAATATGACTCCTT 4 1010 1076032 N/A N/A84424 84439 TATAATTTCCCTGATC 105 1011 1076064 N/A N/A 86676 86691TATGAACAATGTACTC 5 1012 1076096 N/A N/A 90315 90330 AATAATAAACGATTCT 711013 1076128 N/A N/A 92094 92109 TCTAAACCTAAAGACT 118 1014 1076160 N/AN/A 93143 93158 TTATACTAGTACGGCA 20 1015 1076192 N/A N/A 95979 95994CTACAACCTGGACTTT 34 1016 1076224 N/A N/A 97726 97741 TATAAACCTTGCTACA 671017 1076256 N/A N/A 100250 100265 TTATTTAGGCCCCATA 4 1018 1076288 N/AN/A 103352 103367 CTTATTTAGCATAGTG 3 1019 1076320 N/A N/A 105383 105398CATTAACCTCACCCAT 52 1020 1076352 N/A N/A 109308 109323 GATAACCCTGAAACAA37 1021 1076384 N/A N/A 111269 111284 TATAAGGGACTTGCTG 25 1022 1076416N/A N/A 113834 113849 ACCGAAATGATACTGA 8 1023 1076448 N/A N/A 117100117115 CTTATAATGCAATCCT 2 1024 1076480 N/A N/A 119636 119651GTAAATATCCATTACC 72 1025 1076512 N/A N/A 122045 122060 CATAAACCATTAAGTG65 1026 1076544 N/A N/A 71389 71404 GACCAACCTCCCCTTG 89 1027

TABLE 15Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 SEQ CompoundStart Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) UTC) NO 958499 2565 2580 123590 123605ATTAGAGTATGTGGCA 1 810 1074113 98 113 3558 3573 CTCCAACTCCCTTGAC 61 10281074145 286 301 3746 3761 AAGCGGCGACGGCTGC 73 1029 1074177 365 380 38253840 CCTCCCCCGACGCGCA 69 1030 1074209 640 655 4100 4115 CCGGAGCCTCATGGGC72 1031 1074241 921 936 7355 7370 GATGTCTTTGCCATCT 72 1032 1074273 11291144 79070 79085 CTTATGGTTTATATAG 34 1033 1074305 1360 1375 99062 99077CACCTGCCGAAGCAGT 64 1034 1074337 1469 1484 116658 116673GAGTCCCACCATCCTG 10 1035 1074369 1673 1688 N/A N/A TGATAGTATCACCTGT 191036 1074401 1960 1975 122985 123000 TCCGGTGCATGTGTCT 18 1037 10744332258 2273 123283 123298 AAGTCTGAGTATTTAG 5* 1038 1074465 2572 2587123597 123612 AATCTATATTAGAGTA 44 1039 1074497 2744 2759 123769 123784CAATAACCATCCCAAG 26 1040 1074529 3001 3016 124026 124041GCAGACTGCCCCAACC 50 1041 1074561 3176 3191 124201 124216AATTCCAATCGAGACT 10 1042 1074593 3369 3384 124394 124409AGGAGCAAGTCTTGTA 6 1043 1074625 3711 3726 124736 124751 ATAAGGGCTTATTCTA42 1044 1074657 4016 4031 125041 125056 TCCCCCCAGACTTAAT 59 1045 10746894225 4240 125250 125265 CTCCCCCTAAGCTAAA 70 1046 1074721 4404 4419125429 125444 GGAAGATCTCCATATT 43 1047 1074753 4594 4609 125619 125634TACATTAGGAACAAGG 4 1048 1074785 4759 4774 125784 125799 ACCATAAGTAGATCTA10 1049 1074817 5034 5049 126059 126074 CTGAATATTGCCACCC 8 1050 10748495141 5156 126166 126181 TGTTATGATAGGCACA 18 1051 1074913 N/A N/A 55265541 CATCCCGAGTGGGCTA 99 1052 1074945 N/A N/A 5624 5639 CAAAACCCTTTGGTCT74 1053 1074977 N/A N/A 126483 126498 CTTGTTCTATTGGAAG 94 1054 1075009N/A N/A 5287 5302 ATAATCGAACATTGTG 43 1055 1075041 N/A N/A 7620 7635GATTATAAAGAGGCTC 5 1056 1075073 N/A N/A 9719 9734 CATAAAAGTTCCCCAG 511057 1075105 N/A N/A 11110 11125 AATTATAAGGTCCTAC 42 1058 1075137 N/AN/A 13320 13335 GATTAAATACTGACCA 3 1059 1075169 N/A N/A 16611 16626AAAACGGAGTAATGCC 39 1060 1075201 N/A N/A 21864 21879 CTTTAAAGCCCTAATT114 1061 1075233 N/A N/A 24679 24694 GTAATTTATCAGCCAT 2 1062 1075265 N/AN/A 27404 27419 TCTGAATAATATGCAG 44 1063 1075297 N/A N/A 30831 30846GTTAATTATAAGCTGT 10 1064 1075329 N/A N/A 32457 32472 AGGGAAAACTTTGCAC 261065 1075361 N/A N/A 34085 34100 TCTTAAGGGAATGTAT 69 1066 1075393 N/AN/A 36169 36184 CTTAACCTATGCCAAA 37 1067 1075425 N/A N/A 38750 38765ATTATTAATCCTGTCC 26 1068 1075457 N/A N/A 40828 40843 AGTAATATGTACATGG 51069 1075489 N/A N/A 42854 42869 GAGCAACAACTATGAG 51 1070 1075521 N/AN/A 45427 45442 AAATCGAGGCGAATCT 65 1071 1075553 N/A N/A 47527 47542TGATTATAACATGCTG 77 1072 1075585 N/A N/A 49327 49342 AAATAATTGACCTAGC 521073 1075617 N/A N/A 51372 51387 TAAGAACGACATATGC 27 1074 1075649 N/AN/A 52715 52730 CTTCAATAAAGTGGGA 56 1075 1075681 N/A N/A 55170 55185TAATTATTACCCCTTC 37 1076 1075713 N/A N/A 57571 57586 AATCAACCTTGTTAGA 581077 1075745 N/A N/A 59682 59697 CTTCAAAAGCACGGTG 58 1078 1075777 N/AN/A 62196 62211 TATGTGATATGGATTC 12 1079 1075809 N/A N/A 64257 64272TAGCAATAGAGTAACC 13 1080 1075841 N/A N/A 67205 67220 ATTTAGGTACTCAGTA 271081 1075873 N/A N/A 70936 70951 CTTGAATACTACACCA 16 1082 1075905 N/AN/A 73332 73347 CCTGAACACAGGAGTA 43 1083 1075937 N/A N/A 76578 76593ACTTATATTCTCTCCG 36 1084 1075969 N/A N/A 80320 80335 GTATTTAAGCCAAACC 111085 1076001 N/A N/A 82122 82137 ACTCAAGGAACCATTT 24 1086 1076033 N/AN/A 84540 84555 CATTAGTAGGTATTTC 8 1087 1076065 N/A N/A 86761 86776CTTTAGTAACACGAAT 36 1088 1076097 N/A N/A 90316 90331 CAATAATAAACGATTC 701089 1076129 N/A N/A 92131 92146 CATAAACCTTAGTCCT 26 1090 1076161 N/AN/A 93145 93160 TCTTATACTAGTACGG 14 1091 1076193 N/A N/A 96059 96074TTAATACACAGGTTCC 29 1092 1076225 N/A N/A 97727 97742 ATATAAACCTTGCTAC 661093 1076257 N/A N/A 100265 100280 CTAAGAAACTCATAGT 54 1094 1076289 N/AN/A 103430 103445 AACGGACAACTTAACA 21 1095 1076321 N/A N/A 105417 105432CAATATCACTTGGGCC 63 1096 1076353 N/A N/A 109381 109396 ATTAAACATTCGGATT30 1097 1076385 N/A N/A 111270 111285 ATATAAGGGACTTGCT 32 1098 1076417N/A N/A 113840 113855 CTTTACACCGAAATGA 42 1099 1076449 N/A N/A 117101117116 CCTTATAATGCAATCC 2 1100 1076481 N/A N/A 119672 119687CTAAGTAAGGTTTCCC 1 1101 1076513 N/A N/A 122094 122109 CATTAACACTCCTCAG36 1102 1076545 N/A N/A 76624 76639 AACCAACCTTCCCTAC 68 1103

TABLE 16Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 1074114109 124 3569 3584 GAACTTTTTCCCTCCA 30 1104 1074146 287 302 3747 3762GAAGCGGCGACGGCTG 91 1105 1074178 366 381 3826 3841 GCCTCCCCCGACGCGC 951106 1074210 641 656 4101 4116 TCCGGAGCCTCATGGG 113 1107 1074242 925 9407359 7374 AGAAGATGTCTTTGCC 56 1108 1074274 1132 1147 79073 79088GTTCTTATGGTTTATA 4 1109 1074306 1363 1378 99065 99080 CCTCACCTGCCGAAGC107 1110 1074338 1476 1491 116665 116680 GGATTTTGAGTCCCAC 77 11111074370 1674 1689 N/A N/A TTGATAGTATCACCTG 8 1112 1074402 1971 1986122996 123011 TTATGGAAATTTCCGG 25 1113 1074434 2264 2279 123289 123304ACTTCTAAGTCTGAGT 51* 1114 1074466 2651 2666 123676 123691ACCGACCCTGCCAAAA 32 1115 1074498 2745 2760 123770 123785ACAATAACCATCCCAA 17 1116 1074530 3021 3036 124046 124061CTAAACTACTTCAAAC 88 1117 1074562 3177 3192 124202 124217GAATTCCAATCGAGAC 30 1118 1074594 3370 3385 124395 124410TAGGAGCAAGTCTTGT 6 1119 1074626 3730 3745 124755 124770 CTGTTATGAACCCTTG5 1120 1074658 4023 4038 125048 125063 GGCCATTTCCCCCCAG 89 1121 10746904226 4241 125251 125266 CCTCCCCCTAAGCTAA 81 1122 1074722 4405 4420125430 125445 AGGAAGATCTCCATAT 57 1123 1074754 4598 4613 125623 125638CTTTTACATTAGGAAC 11 1124 1074786 4760 4775 125785 125800AACCATAAGTAGATCT 28 1125 1074818 5035 5050 126060 126075ACTGAATATTGCCACC 12 1126 1074850 5142 5157 126167 126182TTGTTATGATAGGCAC 5 1127 1074914 N/A N/A 5529 5544 TTACATCCCGAGTGGG 971128 1074946 N/A N/A 5625 5640 CCAAAACCCTTTGGTC 109 1129 1074978 N/A N/A126492 126507 TTGCCAGTTCTTGTTC 38 1130 1075010 N/A N/A 5288 5303AATAATCGAACATTGT 88 1131 1075042 N/A N/A 7676 7691 TTAAAAGGTTTGGCAC 171132 1075074 N/A N/A 9744 9759 TATAGTAAGACTAATC 105 1133 1075106 N/A N/A11112 11127 CAAATTATAAGGTCCT 10 1134 1075138 N/A N/A 13444 13459AATAATAGATACTGCC 4 1135 1075170 N/A N/A 17299 17314 ACTAAAATCCCCAAGG 941136 1075202 N/A N/A 21884 21899 AATTATATAAGGCTGT 26 1137 1075234 N/AN/A 24701 24716 GTAAATACTCTAGTTC 22 1138 1075266 N/A N/A 27425 27440TATTAGGACAAAGTAC 57 1139 1075298 N/A N/A 30895 30910 ATCTCGGAAATTTAAA128 1140 1075330 N/A N/A 32458 32473 GAGGGAAAACTTTGCA 63 1141 1075362N/A N/A 34134 34149 CAGGAAAAATCTAGGT 50 1142 1075394 N/A N/A 36170 36185TCTTAACCTATGCCAA 27 1143 1075426 N/A N/A 38752 38767 GTATTATTAATCCTGT 491144 1075458 N/A N/A 40971 40986 CCACAATATACTCCAA 7 1145 1075490 N/A N/A42884 42899 CATATACGCAATTAGT 27 1146 1075522 N/A N/A 45428 45443CAAATCGAGGCGAATC 82 1147 1075554 N/A N/A 47574 47589 TTGCAATAGTCACCCA 561148 1075586 N/A N/A 49373 49388 TATTAGCACCTGGGTA 64 1149 1075618 N/AN/A 51375 51390 TTTTAAGAACGACATA 69 1150 1075650 N/A N/A 52783 52798ATATTACAATCCCAGC 48 1151 1075682 N/A N/A 55172 55187 GATAATTATTACCCCT 351152 1075714 N/A N/A 57577 57592 AATTACAATCAACCTT 42 1153 1075746 N/AN/A 59700 59715 GATTAACCCAGTAGAG 28 1154 1075778 N/A N/A 62239 62254CATTTATACCAGGCAC 3 1155 1075810 N/A N/A 64258 64273 GTAGCAATAGAGTAAC 71156 1075842 N/A N/A 67207 67222 GTATTTAGGTACTCAG 2 1157 1075874 N/A N/A71096 71111 CTTAACAACCCTACGA 113 1158 1075906 N/A N/A 73792 73807CCTCAATACAGATGAA 39 1159 1075938 N/A N/A 76754 76769 GAATATATGGGTTTCA 551160 1075970 N/A N/A 80333 80348 GCTTAAAAGGACAGTA 34 1161 1076002 N/AN/A 82141 82156 ATTTAATGGCTTGCAT 21 1162 1076034 N/A N/A 84970 84985AATTAGAAACTTGGCC 74 1163 1076066 N/A N/A 87168 87183 CATATAAGATGTTTGC 81164 1076098 N/A N/A 90319 90334 TTACAATAATAAACGA 94 1165 1076130 N/AN/A 92149 92164 CTGGAATAGTGGGTGC 34 1166 1076162 N/A N/A 93320 93335ATTTACTTGGCAACTC 9 1167 1076194 N/A N/A 96060 96075 TTTAATACACAGGTTC 221168 1076226 N/A N/A 97728 97743 CATATAAACCTTGCTA 36 1169 1076258 N/AN/A 100563 100578 CTTTAGGTGCCTCCTT 10 1170 1076290 N/A N/A 103434 103449CTCCAACGGACAACTT 28 1171 1076322 N/A N/A 106041 106056 ATTTACAAGTGAGCAC21 1172 1076354 N/A N/A 109382 109397 GATTAAACATTCGGAT 13 1173 1076386N/A N/A 111389 111404 AGTTATAACAGTGTAA 7 1174 1076418 N/A N/A 113873113888 TATAATAACCCATTGT 63 1175 1076450 N/A N/A 117136 117151CTTGAATAGCTATGTG 13 1176 1076482 N/A N/A 119679 119694 CTTTAGACTAAGTAAG107 1177 1076514 N/A N/A 122224 122239 CCTTAGGAGATGCACC 18 1178 1076546N/A N/A 79333 79348 CCCCAACCTGAGGAGC 94 1179

TABLE 17Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 SEQ CompoundStart Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) UTC) NO 958499 2565 2580 123590 123605ATTAGAGTATGTGGCA 3 810 1074115 110 125 3570 3585 AGAACTTTTTCCCTCC 331180 1074147 288 303 3748 3763 AGAAGCGGCGACGGCT 23 1181 1074179 383 3983843 3858 CGGGATCCATGGCTTC 49 1182 1074211 643 658 4103 4118CTTCCGGAGCCTCATG 67 1183 1074243 932 947 7366 7381 TCTGACCAGAAGATGT 601184 1074275 1146 1161 79087 79102 CAAGAGGTGGTCTTGT 73 1185 1074307 13671382 99069 99084 GTGGCCTCACCTGCCG 105 1186 1074339 1479 1494 116668116683 ACTGGATTTTGAGTCC 31 1187 1074371 1675 1690 122700 122715GTTGATAGTATCACCT 31 1188 1074403 1973 1988 122998 123013GCTTATGGAAATTTCC 9 1189 1074435 2265 2280 123290 123305 GACTTCTAAGTCTGAG19* 1190 1074467 2652 2667 123677 123692 CACCGACCCTGCCAAA 31 11911074499 2746 2761 123771 123786 TACAATAACCATCCCA 10 1192 1074531 30233038 124048 124063 CACTAAACTACTTCAA 73 1193 1074563 3178 3193 124203124218 TGAATTCCAATCGAGA 4 1194 1074595 3376 3391 124401 124416TAGAAGTAGGAGCAAG 4 1195 1074627 3731 3746 124756 124771 CCTGTTATGAACCCTT3 1196 1074659 4042 4057 125067 125082 CTAAAACTCCATCTGC 12 1197 10746914227 4242 125252 125267 CCCTCCCCCTAAGCTA 76 1198 1074723 4410 4425125435 125450 GGTAAAGGAAGATCTC 6 1199 1074755 4600 4615 125625 125640CACTTTTACATTAGGA 3 1200 1074787 4761 4776 125786 125801 CAACCATAAGTAGATC13 1201 1074819 5039 5054 126064 126079 AAGCACTGAATATTGC 33 1202 10748515143 5158 126168 126183 ATTGTTATGATAGGCA 6 1203 1074915 N/A N/A 55315546 AGTTACATCCCGAGTG 65 1204 1074947 N/A N/A 5626 5641 TCCAAAACCCTTTGGT99 1205 1074979 N/A N/A 126493 126508 ATTGCCAGTTCTTGTT 32 1206 1075011N/A N/A 5292 5307 GCACAATAATCGAACA 44 1207 1075043 N/A N/A 7834 7849CCCCAAAAGCCCTACT 73 1208 1075075 N/A N/A 9942 9957 AATTTTATAAGCCCAC 91209 1075107 N/A N/A 11251 11266 TAAAAACATTGTGGCC 114 1210 1075139 N/AN/A 13448 13463 CCCAAATAATAGATAC 65 1211 1075171 N/A N/A 17320 17335CCCCAATATAAAGAAC 88 1212 1075203 N/A N/A 21885 21900 TAATTATATAAGGCTG 681213 1075235 N/A N/A 24702 24717 AGTAAATACTCTAGTT 38 1214 1075267 N/AN/A 27547 27562 CTATTTAGAATAAGTG 83 1215 1075299 N/A N/A 31204 31219GATAACCAATGCACCA 21 1216 1075331 N/A N/A 32471 32486 GATAAACACTGCAGAG 331217 1075363 N/A N/A 34223 34238 ACACAATATCAAGTCC 25 1218 1075395 N/AN/A 36225 36240 ATGAATAAGTATGCCA 4 1219 1075427 N/A N/A 38797 38812TATAAGGCATCTTGGA 60 1220 1075459 N/A N/A 41050 41065 AACCAAGGATAGTCAT 371221 1075491 N/A N/A 43058 43073 GACGGAAGTTGCAAGG 93 1222 1075523 N/AN/A 45517 45532 AATTAAGGGCCCACAA 78 1223 1075555 N/A N/A 47585 47600GCCAAAAATTCTTGCA 92 1224 1075587 N/A N/A 49375 49390 CTTATTAGCACCTGGG 501225 1075619 N/A N/A 51414 51429 CTTAGATACTACTTTG 54 1226 1075651 N/AN/A 52784 52799 TATATTACAATCCCAG 57 1227 1075683 N/A N/A 55227 55242CTGAAAAAGTTATGCC 56 1228 1075715 N/A N/A 57578 57593 GAATTACAATCAACCT 121229 1075747 N/A N/A 59709 59724 ATTTAGCATGATTAAC 43 1230 1075779 N/AN/A 62290 62305 GTATTACAAACTGATT 28 1231 1075811 N/A N/A 64261 64276ATTGTAGCAATAGAGT 10 1232 1075843 N/A N/A 67232 67247 CATGAAATGATGGAAC 471233 1075875 N/A N/A 71097 71112 ACTTAACAACCCTACG 72 1234 1075907 N/AN/A 73846 73861 AATTACTACTGGCCAT 55 1235 1075939 N/A N/A 76757 76772CTTGAATATATGGGTT 6 1236 1075971 N/A N/A 80380 80395 TATTAACATACCTCAT 281237 1076003 N/A N/A 82142 82157 AATTTAATGGCTTGCA 8 1238 1076035 N/A N/A84972 84987 GTAATTAGAAACTTGG 9 1239 1076067 N/A N/A 87169 87184GCATATAAGATGTTTG 4 1240 1076099 N/A N/A 90414 90429 CCTCAAAACTTGGATT 411241 1076131 N/A N/A 92180 92195 TATTATGAGGACTGAT 23 1242 1076163 N/AN/A 93798 93813 GATATAAGTTACCAAT 16 1243 1076195 N/A N/A 96248 96263AATAACATGGTTCTGT 20 1244 1076227 N/A N/A 97800 97815 ACTTATAAGGCCAGCA 161245 1076259 N/A N/A 100700 100715 ATTTAACTCCTGAAGT 61 1246 1076291 N/AN/A 103541 103556 GATTAATGGTGGCATT 4 1247 1076323 N/A N/A 106043 106058CAATTTACAAGTGAGC 5 1248 1076355 N/A N/A 109562 109577 CTACAAAAGAGCTATG92 1249 1076387 N/A N/A 111398 111413 TGACAACACAGTTATA 13 1250 1076419N/A N/A 113874 113889 ATATAATAACCCATTG 47 1251 1076451 N/A N/A 117183117198 CCTTAAGAACATGAGG 77 1252 1076483 N/A N/A 119774 119789ACGGGAAATCATATAG 5 1253 1076515 N/A N/A 122246 122261 CTGCAAGAATACTTTA30 1254 1076547 N/A N/A 97024 97039 GACCAACCTCCCTCAG 89 1255

TABLE 18 Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074116111 126 3571 3586 GAGAACTTTTTCCCTC 112 1256 1074148 292 307 3752 3767GTGGAGAAGCGGCGAC 66 1257 1074180 384 399 3844 3859 CCGGGATCCATGGCTT 861258 1074212 644 659 4104 4119 GCTTCCGGAGCCTCAT 53 1259 1074244 933 9487367 7382 CTCTGACCAGAAGATG 95 1260 1074276 1147 1162 79088 79103CCAAGAGGTGGTCTTG 87 1261 1074308 1376 1391 N/A N/A GCATTGCCTGTGGCCT 1321262 1074340 1493 1508 116682 116697 TCCCGGGAGAAGACAC 120 1263 10743721680 1695 122705 122720 CTTTGGTTGATAGTAT 10 1264 1074404 1974 1989122999 123014 GGCTTATGGAAATTTC 16 1265 1074436 2277 2292 123302 123317CATGAAGCATCTGACT 31* 1266 1074468 2653 2668 123678 123693CCACCGACCCTGCCAA 34 1267 1074500 2747 2762 123772 123787CTACAATAACCATCCC 10 1268 1074532 3026 3041 124051 124066GAACACTAAACTACTT 59 1269 1074564 3179 3194 124204 124219CTGAATTCCAATCGAG 4 1270 1074596 3401 3416 124426 124441 TTCTATCCAGGGTCAA12 1271 1074628 3732 3747 124757 124772 GCCTGTTATGAACCCT 5 1272 10746604057 4072 125082 125097 AATTTCATTACTACTC 48 1273 1074692 4245 4260125270 125285 CCCCCCCAAACTTTCC 101 1274 1074724 4411 4426 125436 125451GGGTAAAGGAAGATCT 22 1275 1074756 4601 4616 125626 125641GCACTTTTACATTAGG 3 1276 1074788 4762 4777 125787 125802 TCAACCATAAGTAGAT25 1277 1074820 5046 5061 126071 126086 AAGTGTTAAGCACTGA 85 1278 10748525144 5159 126169 126184 AATTGTTATGATAGGC 4 1279 1074916 N/A N/A 55325547 AAGTTACATCCCGAGT 75 1280 1074948 N/A N/A 5630 5645 GAGTTCCAAAACCCTT61 1281 1074980 N/A N/A 126494 126509 TATTGCCAGTTCTTGT 26 1282 1075012N/A N/A 5349 5364 CTATTGGAATGTTAAC 119 1283 1075044 N/A N/A 7844 7859AATTAGACTCCCCCAA 58 1284 1075076 N/A N/A 10048 10063 CATAACATCATGGAAG 251285 1075108 N/A N/A 11252 11267 CTAAAAACATTGTGGC 67 1286 1075140 N/AN/A 13661 13676 CTTTAGGTTAAGCAAT 86 1287 1075172 N/A N/A 17404 17419CTTTACATGAACTGAT 14 1288 1075204 N/A N/A 22115 22130 GTTAAACACATCTCAG 431289 1075236 N/A N/A 24827 24842 TATAATACCACAAAGT 81 1290 1075268 N/AN/A 27596 27611 TATTAACCTGGAGAGT 47 1291 1075300 N/A N/A 31414 31429CGTGAAAAGAAAGGCC 98 1292 1075332 N/A N/A 32520 32535 AGCGGGTTTAGAATGC 661293 1075364 N/A N/A 34293 34308 CGAAAATAGTTCTCAA 59 1294 1075396 N/AN/A 36570 36585 ATTATCGCACATACAT 89 1295 1075428 N/A N/A 38799 38814TATATAAGGCATCTTG 53 1296 1075460 N/A N/A 41053 41068 AATAACCAAGGATAGT 301297 1075492 N/A N/A 43309 43324 GCTAAAATGATACTTC 29 1298 1075524 N/AN/A 45518 45533 TAATTAAGGGCCCACA 71 1299 1075556 N/A N/A 47618 47633TGGCAAAAGAGTGGTG 68 1300 1075588 N/A N/A 49376 49391 ACTTATTAGCACCTGG 271301 1075620 N/A N/A 51476 51491 GATGAAGAATCTATAG 88 1302 1075652 N/AN/A 52785 52800 GTATATTACAATCCCA 40 1303 1075684 N/A N/A 55228 55243TCTGAAAAAGTTATGC 78 1304 1075716 N/A N/A 57654 57669 GCCGAAATACTCTCAT 191305 1075748 N/A N/A 59723 59738 GTAAATCAAGTTGCAT 7 1306 1075780 N/A N/A62440 62455 TATAATAATCCAGAAC 98 1307 1075812 N/A N/A 64470 64485CATTAAGATTTTAACC 103 1308 1075844 N/A N/A 67247 67262 TATTAAATAAGAGCTC84 1309 1075876 N/A N/A 71176 71191 GTATTTATGATGATTC 6 1310 1075908 N/AN/A 74518 74533 AATAAGGAGTAGGTGG 50 1311 1075940 N/A N/A 77113 77128ACTCAACAACCCCAAG 54 1312 1075972 N/A N/A 80426 80441 TCACAAGGGCTAATTC 221313 1076004 N/A N/A 82143 82158 TAATTTAATGGCTTGC 2 1314 1076036 N/A N/A84973 84988 CGTAATTAGAAACTTG 19 1315 1076068 N/A N/A 87383 87398CTAAAATGACCTTAGC 73 1316 1076100 N/A N/A 90552 90567 AATAAGGGACTACTTT 651317 1076132 N/A N/A 92207 92222 CATCAATACTGACATC 28 1318 1076164 N/AN/A 93799 93814 TGATATAAGTTACCAA 50 1319 1076196 N/A N/A 96347 96362TATCAAGGGAATTATT 113 1320 1076228 N/A N/A 98039 98054 ATTAACCTCAGTGAGC69 1321 1076260 N/A N/A 100704 100719 CTTAATTTAACTCCTG 3 1322 1076292N/A N/A 103572 103587 TATTATTGAGTTATCC 27 1323 1076324 N/A N/A 106059106074 GCTCAAAAGGTCTCTC 13 1324 1076356 N/A N/A 109576 109591CATAATTGGACTGTCT 99 1325 1076388 N/A N/A 111483 111498 GAAATATTCGAGAAGA6 1326 1076420 N/A N/A 113876 113891 CCATATAATAACCCAT 26 1327 1076452N/A N/A 117193 117208 GGACTATAGCCCTTAA 16 1328 1076484 N/A N/A 119777119792 GAAACGGGAAATCATA 10 1329 1076516 N/A N/A 122314 122329CATAAACATGAGTGGT 8 1330 1076548 N/A N/A 116744 116759 CACCAACCTGTTAAGG106 1331

TABLE 19Inhibition of Yap 1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 SEQ CompoundStart Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) UTC) NO 958499 2565 2580 123590 123605ATTAGAGTATGTGGCA 2 810 1074117 117 132 3577 3592 GCGCCTGAGAACTTTT 871332 1074149 298 313 3758 3773 GCCGAGGTGGAGAAGC 58 1333 1074181 385 4003845 3860 CCCGGGATCCATGGCT 107 1334 1074213 654 669 4114 4129GAGTCGGGCAGCTTCC 55 1335 1074245 941 956 7375 7390 AGAAGTATCTCTGACC 51336 1074277 1153 1168 79094 79109 GTCTAGCCAAGAGGTG 18 1337 1074309 13781393 N/A N/A CCGCATTGCCTGTGGC 80 1338 1074341 1494 1509 116683 116698ATCCCGGGAGAAGACA 106 1339 1074373 1681 1696 122706 122721GCTTTGGTTGATAGTA 26 1340 1074405 1991 2006 123016 123031GCCTGAAAACTGCAAC 27 1341 1074437 2278 2293 123303 123318ACATGAAGCATCTGAC 4* 1342 1074469 2654 2669 123679 123694CCCACCGACCCTGCCA 77 1343 1074501 2748 2763 123773 123788ACTACAATAACCATCC 9 1344 1074533 3028 3043 124053 124068 TAGAACACTAAACTAC80 1345 1074565 3180 3195 124205 124220 ACTGAATTCCAATCGA 5 1346 10745973405 3420 124430 124445 AGTATTCTATCCAGGG 5 1347 1074629 3742 3757 124767124782 GAGATTTTATGCCTGT 3 1348 1074661 4058 4073 125083 125098GAATTTCATTACTACT 36 1349 1074693 4246 4261 125271 125286CCCCCCCCAAACTTTC 92 1350 1074725 4437 4452 125462 125477GTATAACTGGGCAAAT 17 1351 1074757 4607 4622 125632 125647AGTTAAGCACTTTTAC 21 1352 1074789 4763 4778 125788 125803ATCAACCATAAGTAGA 17 1353 1074821 5049 5064 126074 126089GAAAAGTGTTAAGCAC 18 1354 1074853 5145 5160 126170 126185CAATTGTTATGATAGG 15 1355 1074917 N/A N/A 5533 5548 CAAGTTACATCCCGAG 801356 1074949 N/A N/A 5642 5657 GTGATTTTTTCTGAGT 31 1357 1074981 N/A N/A126495 126510 TTATTGCCAGTTCTTG 9 1358 1075013 N/A N/A 5768 5783CATAAACCCACTTCGA 102 1359 1075045 N/A N/A 7845 7860 AAATTAGACTCCCCCA 181360 1075077 N/A N/A 10057 10072 TATACGGTCCATAACA 35 1361 1075109 N/AN/A 11253 11268 ACTAAAAACATTGTGG 71 1362 1075141 N/A N/A 13863 13878TATACGAGAAGTTGAA 54 1363 1075173 N/A N/A 17464 17479 CTTTAGGGCAACTGTA 221364 1075205 N/A N/A 22160 22175 ATTAAATGAGCACCAC 29 1365 1075237 N/AN/A 25230 25245 GCTGAAAATGCTAACT 105 1366 1075269 N/A N/A 27597 27612TTATTAACCTGGAGAG 13 1367 1075301 N/A N/A 31460 31475 CAGCAACACCTAAGGA 921368 1075333 N/A N/A 32529 32544 AGTTAACAAAGCGGGT 14 1369 1075365 N/AN/A 34295 34310 CACGAAAATAGTTCTC 11 1370 1075397 N/A N/A 36571 36586CATTATCGCACATACA 79 1371 1075429 N/A N/A 38974 38989 CTTTACTATCTGGGTC 231372 1075461 N/A N/A 41056 41071 CTAAATAACCAAGGAT 64 1373 1075493 N/AN/A 43320 43335 AGACAAGGGATGCTAA 67 1374 1075525 N/A N/A 45519 45534TTAATTAAGGGCCCAC 130 1375 1075557 N/A N/A 47655 47670 TATTAAGGTGGCTTAC57 1376 1075589 N/A N/A 49390 49405 AATTAGCAGGGCAGAC 84 1377 1075621 N/AN/A 51645 51660 GATTAACATTGATACT 61 1378 1075653 N/A N/A 53476 53491CATAAACTCTGCTGTC 58 1379 1075685 N/A N/A 55369 55384 CATAATCAAAGGGTGC 601380 1075717 N/A N/A 57665 57680 CATAAATTTCAGCCGA 10 1381 1075749 N/AN/A 59800 59815 AATTATGAATGATGGG 4 1382 1075781 N/A N/A 62475 62490CATATATTGTGACTTC 2 1383 1075813 N/A N/A 64652 64667 ACTAATATGCAACTCT 41384 1075845 N/A N/A 67654 67669 GTGGAAAAGTATGATC 19 1385 1075877 N/AN/A 71248 71263 CTGGAAAAGTACATTC 28 1386 1075909 N/A N/A 74519 74534AAATAAGGAGTAGGTG 93 1387 1075941 N/A N/A 77150 77165 AGTCAATAGCAATCAC 111388 1075973 N/A N/A 80581 80596 CCGCAACACCATTCTT 8 1389 1076005 N/A N/A82193 82208 GTACAAAATCTCCAGG 69 1390 1076037 N/A N/A 84987 85002CTTAAATTCTCTTACG 21 1391 1076069 N/A N/A 87384 87399 TCTAAAATGACCTTAG118 1392 1076101 N/A N/A 90553 90568 AAATAAGGGACTACTT 71 1393 1076133N/A N/A 92254 92269 CATACTAATTTGGTAA 60 1394 1076165 N/A N/A 93923 93938CCCCAAGGACTTGCCA 79 1395 1076197 N/A N/A 96350 96365 TATTATCAAGGGAATT 941396 1076229 N/A N/A 98040 98055 AATTAACCTCAGTGAG 91 1397 1076261 N/AN/A 100852 100867 CCCCAACAAGTTCCTG 39 1398 1076293 N/A N/A 103575 103590GCTTATTATTGAGTTA 3 1399 1076325 N/A N/A 106620 106635 CTAATAATGGAAGAGT16 1400 1076357 N/A N/A 109680 109695 TCCAAAAACTTCTTAG 22 1401 1076389N/A N/A 111486 111501 ATCGAAATATTCGAGA 76 1402 1076421 N/A N/A 113900113915 AATTATGACCTCCATG 65 1403 1076453 N/A N/A 117330 117345GTAATATTGCAATCTG 1 1404 1076485 N/A N/A 119781 119796 AAACGAAACGGGAAAT55 1405 1076517 N/A N/A 122329 122344 CATAATAAGACTAAAC 102 1406 1076549N/A N/A 117537 117552 GTGCAAAATACCTTTG 8 1407

TABLE 20 Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ ID Number Site Site Site Site Sequence (5′ to 3′)UTC) NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074118131 146 3591 3606 CACTCGGACCTGCGGC 66 1408 1074150 299 314 3759 3774GGCCGAGGTGGAGAAG 85 1409 1074182 386 401 3846 3861 GCCCGGGATCCATGGC 821410 1074214 672 687 4132 4147 TCCGGCGGCTTGAAGA 89 1411 1074246 942 9577376 7391 AAGAAGTATCTCTGAC 11 1412 1074278 1158 1173 79099 79114CTTGGGTCTAGCCAAG 31 1413 1074310 1379 1394 N/A N/A TCCGCATTGCCTGTGG 1001414 1074342 1495 1510 116684 116699 CATCCCGGGAGAAGAC 56 1415 10743741682 1697 122707 122722 TGCTTTGGTTGATAGT 13 1416 1074406 2032 2047123057 123072 AAAGTATCTTGCTGGA 16 1417 1074438 2279 2294 123304 123319GACATGAAGCATCTGA 1* 1418 1074470 2657 2672 123682 123697CCCCCCACCGACCCTG 69 1419 1074502 2749 2764 123774 123789AACTACAATAACCATC 31 1420 1074534 3041 3056 124066 124081TAATAGCTCTTTCTAG 88 1421 1074566 3181 3196 124206 124221CACTGAATTCCAATCG 3 1422 1074598 3410 3425 124435 124450 CTTATAGTATTCTATC46 1423 1074630 3743 3758 124768 124783 AGAGATTTTATGCCTG 5 1424 10746624062 4077 125087 125102 GGTAGAATTTCATTAC 30 1425 1074694 4247 4262125272 125287 CCCCCCCCCAAACTTT 79 1426 1074726 4438 4453 125463 125478GGTATAACTGGGCAAA 2 1427 1074758 4608 4623 125633 125648 CAGTTAAGCACTTTTA4 1428 1074790 4764 4779 125789 125804 CATCAACCATAAGTAG 28 1429 10748225051 5066 126076 126091 TAGAAAAGTGTTAAGC 25 1430 1074854 5146 5161126171 126186 ACAATTGTTATGATAG 23 1431 1074918 N/A N/A 5534 5549TCAAGTTACATCCCGA 60 1432 1074950 N/A N/A 5652 5667 ATCAGGTTAAGTGATT 1201433 1074982 N/A N/A 126500 126515 ACCTTTTATTGCCAGT 13 1434 1075014 N/AN/A 6038 6053 GGAGAAATAAAAGTCG 46 1435 1075046 N/A N/A 7846 7861AAAATTAGACTCCCCC 12 1436 1075078 N/A N/A 10061 10076 CAACTATACGGTCCAT 31437 1075110 N/A N/A 11254 11269 GACTAAAAACATTGTG 120 1438 1075142 N/AN/A 13865 13880 GATATACGAGAAGTTG 16 1439 1075174 N/A N/A 17491 17506CCTGAAAAGACAGTCC 74 1440 1075206 N/A N/A 22161 22176 TATTAAATGAGCACCA 361441 1075238 N/A N/A 25596 25611 CTTAAACAGGTGCCAA 24 1442 1075270 N/AN/A 27599 27614 CTTTATTAACCTGGAG 18 1443 1075302 N/A N/A 31497 31512CCTTAAAGCTTCCACC 75 1444 1075334 N/A N/A 32542 32557 TTAATAATCTACCAGT 601445 1075366 N/A N/A 34296 34311 ACACGAAAATAGTTCT 27 1446 1075398 N/AN/A 36612 36627 TATATATGGCCCTTTA 49 1447 1075430 N/A N/A 39017 39032CTTAACTAACTTGACC 96 1448 1075462 N/A N/A 41259 41274 GTTTATAGACAAGTCA 151449 1075494 N/A N/A 43450 43465 TCTCAACAATTTGCTA 47 1450 1075526 N/AN/A 45520 45535 TTTAATTAAGGGCCCA 110 1451 1075558 N/A N/A 47656 47671ATATTAAGGTGGCTTA 51 1452 1075590 N/A N/A 49396 49411 CATCAAAATTAGCAGG 501453 1075622 N/A N/A 51771 51786 TCTTATACCTATCTTC 56 1454 1075654 N/AN/A 53501 53516 TATTAAGACGAATCCA 76 1455 1075686 N/A N/A 55578 55593GTAATTACAGTGTCTC 10 1456 1075718 N/A N/A 57703 57718 CCACTAAAACCAAGTT 481457 1075750 N/A N/A 59801 59816 CAATTATGAATGATGG 10 1458 1075782 N/AN/A 62506 62521 TATTAGGTTTCCCGTT 10 1459 1075814 N/A N/A 64821 64836TATAAAGCAGGGCATT 47 1460 1075846 N/A N/A 67670 67685 GATTAAGAGCCTATCT 961461 1075878 N/A N/A 71286 71301 GATTATCAAGTAGTTT 35 1462 1075910 N/AN/A 74520 74535 GAAATAAGGAGTAGGT 93 1463 1075942 N/A N/A 77172 77187TGACTATACATGGTGA 46 1464 1075974 N/A N/A 80589 80604 AAAAAATTCCGCAACA 391465 1076006 N/A N/A 82219 82234 TTTAAACCTGAGACTC 41 1466 1076038 N/AN/A 85047 85062 AGGCAAGAATTGGGTA 11 1467 1076070 N/A N/A 87434 87449ATTAGTAATGCACAGG 6 1468 1076102 N/A N/A 90613 90628 CTTAACAAATCAGCCC 321469 1076134 N/A N/A 92267 92282 GATTAGAGTTGGGCAT 10 1470 1076166 N/AN/A 93997 94012 ATTTACACCACCGCCC 77 1471 1076198 N/A N/A 96351 96366CTATTATCAAGGGAAT 81 1472 1076230 N/A N/A 98041 98056 GAATTAACCTCAGTGA 501473 1076262 N/A N/A 101120 101135 AGACAATAGTCTGGGC 41 1474 1076294 N/AN/A 103629 103644 TATATTAGTGCCCCCT 6 1475 1076326 N/A N/A 106621 106636GCTAATAATGGAAGAG 4 1476 1076358 N/A N/A 109745 109760 GTTTAACAAACTTGTA43 1477 1076390 N/A N/A 111487 111502 GATCGAAATATTCGAG 54 1478 1076422N/A N/A 113901 113916 GAATTATGACCTCCAT 13 1479 1076454 N/A N/A 117469117484 TAAACTAATCCCATAT 35 1480 1076486 N/A N/A 119782 119797GAAACGAAACGGGAAA 5 1481 1076518 N/A N/A 122341 122356 GATAAGCACCACCATA25 1482 1076550 N/A N/A 120573 120588 TACCAACCTGTATCCA 61 1483

TABLE 21Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074119132 147 3592 3607 GCACTCGGACCTGCGG 71 1484 1074151 300 315 3760 3775GGGCCGAGGTGGAGAA 81 1485 1074183 407 422 3867 3882 CCGGTTGAGGCGGCGG 901486 1074215 674 689 4134 4149 GCTCCGGCGGCTTGAA 77 1487 1074247 955 970N/A N/A ATCGATGTGATTTAAG 43 1488 1074279 1165 1180 79106 79121GTCAAGCCTTGGGTCT 13 1489 1074311 1380 1395 N/A N/A TTCCGCATTGCCTGTG 241490 1074343 1498 1513 116687 116702 AGACATCCCGGGAGAA 18 1491 10743751688 1703 122713 122728 GCAGGGTGCTTTGGTT 33 1492 1074407 2033 2048123058 123073 TAAAGTATCTTGCTGG 6 1493 1074439 2283 2298 123308 123323CTGTGACATGAAGCAT 2* 1494 1074471 2658 2673 123683 123698CCCCCCCACCGACCCT 69 1495 1074503 2750 2765 123775 123790CAACTACAATAACCAT 29 1496 1074535 3042 3057 124067 124082GTAATAGCTCTTTCTA 5 1497 1074567 3189 3204 124214 124229 AACCTACTCACTGAAT38 1498 1074599 3423 3438 124448 124463 GCTAACTCAAAACCTT 12 1499 10746313765 3780 124790 124805 CATAGCAGCTTTTGCC 9 1500 1074663 4069 4084 125094125109 CATTCTAGGTAGAATT 79 1501 1074695 4266 4281 125291 125306CCCCCTAAATCTTCAC 49 1502 1074727 4440 4455 125465 125480GAGGTATAACTGGGCA 9 1503 1074759 4619 4634 125644 125659 CAACCAAGAAGCAGTT43 1504 1074791 4767 4782 125792 125807 CTCCATCAACCATAAG 20 1505 10748235080 5095 126105 126120 GAGCACTCATTTCTCA 77 1506 1074855 5213 5228126238 126253 GTGCATTAAAGAATTC 29 1507 1074887 N/A N/A 5450 5465TAGCCTGAAGCAAGTT 57 1508 1074919 N/A N/A 5535 5550 CTCAAGTTACATCCCG 481509 1074951 N/A N/A 5653 5668 CATCAGGTTAAGTGAT 85 1510 1074983 N/A N/A126501 126516 CACCTTTTATTGCCAG 11 1511 1075015 N/A N/A 6067 6082CAGAATAAGTATGATT 55 1512 1075047 N/A N/A 7847 7862 TAAAATTAGACTCCCC 71513 1075079 N/A N/A 10149 10164 CACCAAAAGCTTAGTT 40 1514 1075111 N/AN/A 11385 11400 TAGGAATATGGGTAGT 5 1515 1075143 N/A N/A 13883 13898CCTTATTAGTCAGTTC 2 1516 1075175 N/A N/A 17507 17522 ACTGAAAGATTCCATG 991517 1075207 N/A N/A 22162 22177 CTATTAAATGAGCACC 4 1518 1075239 N/A N/A25597 25612 TCTTAAACAGGTGCCA 27 1519 1075271 N/A N/A 27652 27667GATGTGATCTGTGAGA 11 1520 1075303 N/A N/A 31554 31569 TAAACTAATCTACAAC100 1521 1075335 N/A N/A 32543 32558 CTTAATAATCTACCAG 30 1522 1075367N/A N/A 34502 34517 CATTACTTAGGGCTTA 12 1523 1075399 N/A N/A 36614 36629CATATATATGGCCCTT 15 1524 1075431 N/A N/A 39045 39060 TAACTAAACTGATTCC 741525 1075463 N/A N/A 41370 41385 CTTAATCCAAAGCTTC 34 1526 1075495 N/AN/A 43489 43504 CTTAATTGGTAACTGA 19 1527 1075527 N/A N/A 45521 45536ATTTAATTAAGGGCCC 82 1528 1075559 N/A N/A 47657 47672 GATATTAAGGTGGCTT 241529 1075591 N/A N/A 49541 49556 GTAATAATCACCTTAC 76 1530 1075623 N/AN/A 51815 51830 CATAATCAAAATGGGC 48 1531 1075655 N/A N/A 53502 53517CTATTAAGACGAATCC 38 1532 1075687 N/A N/A 55642 55657 TAAACGAGTAATGACT 231533 1075719 N/A N/A 58015 58030 CTAAAACCGGCTGGAC 76 1534 1075751 N/AN/A 59839 59854 GAGGAACAAGATCTCA 72 1535 1075783 N/A N/A 62684 62699CTTAATTTACCTGAAC 36 1536 1075815 N/A N/A 64822 64837 GTATAAAGCAGGGCAT 361537 1075847 N/A N/A 67823 67838 CTTTATAGCAGATGCC 14 1538 1075879 N/AN/A 71353 71368 GAATAAAGAAGTCACC 77 1539 1075911 N/A N/A 74637 74652TGACAAAACAGGCACC 41 1540 1075943 N/A N/A 77361 77376 GTATATCAAACCTTTT 151541 1075975 N/A N/A 80592 80607 GGAAAAAAATTCCGCA 84 1542 1076007 N/AN/A 82293 82308 CATTAGGCCTTTTACT 27 1543 1076039 N/A N/A 85200 85215GATTAGAGCTGTATTC 29 1544 1076071 N/A N/A 87435 87450 TATTAGTAATGCACAG 141545 1076103 N/A N/A 90614 90629 GCTTAACAAATCAGCC 79 1546 1076135 N/AN/A 92319 92334 CATAATTGACAGGTAT 14 1547 1076167 N/A N/A 93999 94014AAATTTACACCACCGC 33 1548 1076199 N/A N/A 96382 96397 TATCAAAAGTCCATCC 371549 1076231 N/A N/A 98106 98121 TTAGAAATGGACTGGG 16 1550 1076263 N/AN/A 101298 101313 AATAACCAAGTGAGTT 21 1551 1076295 N/A N/A 103630 103645GTATATTAGTGCCCCC 2 1552 1076327 N/A N/A 106694 106709 GATAAGCAAGGTTCTC 71553 1076359 N/A N/A 109776 109791 ATTTATCCTAGTTACC 29 1554 1076391 N/AN/A 111530 111545 CAAATATAGTTAGCCT 22 1555 1076423 N/A N/A 114068 114083CCTGAACCTTCTGGAT 93 1556 1076455 N/A N/A 117635 117650 ACTAAATACTTTTAGC86 1557 1076487 N/A N/A 119786 119801 GTACGAAACGAAACGG 21 1558 1076519N/A N/A 122375 122390 ACACAACACGACAGCA 31 1559 1076551 N/A N/A 5268 5283GTGGAATAGCAGCCAT 67 1560

TABLE 22 Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074120137 152 3597 3612 GCGAGGCACTCGGACC 50 1561 1074152 301 316 3761 3776CGGGCCGAGGTGGAGA 77 1562 1074184 408 423 3868 3883 GCCGGTTGAGGCGGCG 1001563 1074216 681 696 4141 4156 GATTTGGGCTCCGGCG 58 1564 1074248 956 971N/A N/A GATCGATGTGATTTAA 29 1565 1074280 1166 1181 79107 79122GGTCAAGCCTTGGGTC 43 1566 1074312 1383 1398 102515 102530ATATTCCGCATTGCCT 18 1567 1074344 1500 1515 116689 116704TGAGACATCCCGGGAG 99 1568 1074376 1706 1721 122731 122746AACGGTTCTGCTGTGA 44 1569 1074408 2036 2051 123061 123076GATTAAAGTATCTTGC 23 1570 1074440 2284 2299 123309 123324GCTGTGACATGAAGCA 38* 1571 1074472 2660 2675 123685 123700AACCCCCCCACCGACC 107 1572 1074504 2804 2819 123829 123844TCGAGATTTAAATAAG 76 1573 1074536 3043 3058 124068 124083AGTAATAGCTCTTTCT 6 1574 1074568 3190 3205 124215 124230 GAACCTACTCACTGAA12 1575 1074600 3425 3440 124450 124465 CAGCTAACTCAAAACC 29 1576 10746323766 3781 124791 124806 TCATAGCAGCTTTTGC 12 1577 1074664 4070 4085125095 125110 GCATTCTAGGTAGAAT 49 1578 1074696 4268 4283 125293 125308GTCCCCCTAAATCTTC 38 1579 1074728 4441 4456 125466 125481TGAGGTATAACTGGGC 3 1580 1074760 4620 4635 125645 125660 ACAACCAAGAAGCAGT11 1581 1074792 4776 4791 125801 125816 ATCAATGTGCTCCATC 4 1582 10748245083 5098 126108 126123 CCTGAGCACTCATTTC 53 1583 1074856 5223 5238126248 126263 TTTGACAAGTGTGCAT 15 1584 1074888 N/A N/A 5453 5468GTTTAGCCTGAAGCAA 58 1585 1074920 N/A N/A 5536 5551 ACTCAAGTTACATCCC 681586 1074952 N/A N/A 5661 5676 GTTTTTGTCATCAGGT 42 1587 1074984 N/A N/A126503 126518 ATCACCTTTTATTGCC 31 1588 1075016 N/A N/A 6068 6083TCAGAATAAGTATGAT 100 1589 1075048 N/A N/A 7848 7863 GTAAAATTAGACTCCC 41590 1075080 N/A N/A 10219 10234 ATTACAAAGACAGCCC 18 1591 1075112 N/AN/A 11388 11403 ATATAGGAATATGGGT 6 1592 1075144 N/A N/A 14659 14674ACCCTATATCCTATAT 82 1593 1075176 N/A N/A 17544 17559 AATTACCCGGGAACTA 701594 1075208 N/A N/A 22191 22206 ACTGAACACAGGCTAC 24 1595 1075240 N/AN/A 25749 25764 TAAACGGTTTATATTC 16 1596 1075272 N/A N/A 28023 28038AATTAGCCAGCATGCA 110 1597 1075304 N/A N/A 31613 31628 CACGGGTACCAGAAAA50 1598 1075336 N/A N/A 32544 32559 GCTTAATAATCTACCA 32 1599 1075368 N/AN/A 34751 34766 GAGAATAAGCAATCAG 24 1600 1075400 N/A N/A 36641 36656TAGCAATAGTCAGGTA 11 1601 1075432 N/A N/A 39046 39061 CTAACTAAACTGATTC121 1602 1075464 N/A N/A 41448 41463 CCACTAAACCACCTAA 77 1603 1075496N/A N/A 43503 43518 TTATATAATGCAGGCT 22 1604 1075528 N/A N/A 45616 45631ATCGAAGGGCAAACTC 42 1605 1075560 N/A N/A 47723 47738 GCTAAATAAAGGTTAC 861606 1075592 N/A N/A 49542 49557 CGTAATAATCACCTTA 55 1607 1075624 N/AN/A 51848 51863 ATCTATAACCCTTATT 91 1608 1075656 N/A N/A 53591 53606AAAACGGTTTTTCTAA 103 1609 1075688 N/A N/A 55673 55688 GACAATAAACATCACC12 1610 1075720 N/A N/A 58458 58473 CTTTACTACATATAGC 47 1611 1075752 N/AN/A 60020 60035 CATAATTATACTGATC 19 1612 1075784 N/A N/A 62703 62718ATTTTATAGGGCCATT 3 1613 1075816 N/A N/A 64824 64839 TAGTATAAAGCAGGGC 71614 1075848 N/A N/A 67963 67978 GATTACAATGGGCAGT 9 1615 1075880 N/A N/A71412 71427 ATTAACTACACCACGA 30 1616 1075912 N/A N/A 74743 74758AGTTATACACAACCAC 13 1617 1075944 N/A N/A 77599 77614 TATTAGGAACAGATCA 251618 1075976 N/A N/A 80964 80979 ATTAAAAGTCGGGCCA 92 1619 1076008 N/AN/A 82386 82401 AGCGAAAATAACATTA 33 1620 1076040 N/A N/A 85319 85334CTTAAAGAAGCACTAG 105 1621 1076072 N/A N/A 87726 87741 CACAAAAACTGGTCTG18 1622 1076104 N/A N/A 90640 90655 ACGAAATAGTAACTGT 24 1623 1076136 N/AN/A 92372 92387 CAACAACCTCATGTAA 60 1624 1076168 N/A N/A 94000 94015CAAATTTACACCACCG 23 1625 1076200 N/A N/A 96417 96432 GATTACACTATCAAAA 671626 1076232 N/A N/A 98125 98140 GTAATACACCATTTGG 15 1627 1076264 N/AN/A 101302 101317 ACCCAATAACCAAGTG 40 1628 1076296 N/A N/A 103670 103685TATAAAGACCCAATGC 68 1629 1076328 N/A N/A 107005 107020 ACTGAACCGCTGCCTC33 1630 1076360 N/A N/A 109778 109793 CTATTTATCCTAGTTA 59 1631 1076392N/A N/A 111564 111579 TATTAATCAAATAGGG 64 1632 1076424 N/A N/A 114085114100 ACTTAACCTGACAGCT 76 1633 1076456 N/A N/A 117763 117778CTTTAAAGTGTATGTC 2 1634 1076488 N/A N/A 119867 119882 GCCAATAAGATAAGAA19 1635 1076520 N/A N/A 122407 122422 AATTATATGCAGCAGC 21 1636 1076552N/A N/A 11807 11822 ATGTATAAATACCAGG 7 1637

TABLE 23Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 1074121138 153 3598 3613 TGCGAGGCACTCGGAC 87 1638 1074153 303 318 3763 3778CACGGGCCGAGGTGGA 78 1639 1074185 409 424 3869 3884 GGCCGGTTGAGGCGGC 911640 1074217 682 697 4142 4157 GGATTTGGGCTCCGGC 74 1641 1074249 957 972N/A N/A TGATCGATGTGATTTA 23 1642 1074281 1169 1184 79110 79125GAGGGTCAAGCCTTGG 91 1643 1074313 1385 1400 102517 102532TGATATTCCGCATTGC 5 1644 1074345 1533 1548 116722 116737 TCTGAGCTATTGGTCG8 1645 1074377 1707 1722 122732 122747 AAACGGTTCTGCTGTG 52 1646 10744092037 2052 123062 123077 GGATTAAAGTATCTTG 6 1647 1074441 2294 2309 123319123334 CAAACTAAATGCTGTG 5* 1648 1074473 2661 2676 123686 123701CAACCCCCCCACCGAC 82 1649 1074505 2806 2821 123831 123846AATCGAGATTTAAATA 83 1650 1074537 3044 3059 124069 124084CAGTAATAGCTCTTTC 3 1651 1074569 3191 3206 124216 124231 TGAACCTACTCACTGA8 1652 1074601 3426 3441 124451 124466 CCAGCTAACTCAAAAC 24 1653 10746333774 3789 124799 124814 GAGGCTTTTCATAGCA 78 1654 1074665 4072 4087125097 125112 TTGCATTCTAGGTAGA 17 1655 1074697 4274 4289 125299 125314ATCAAGGTCCCCCTAA 44 1656 1074729 4445 4460 125470 125485ACACTGAGGTATAACT 9 1657 1074761 4628 4643 125653 125668 TACCCAATACAACCAA15 1658 1074793 4777 4792 125802 125817 AATCAATGTGCTCCAT 9 1659 10748255084 5099 126109 126124 ACCTGAGCACTCATTT 36 1660 1074857 5245 5260126270 126285 ACATTGGTACTATATA 25 1661 1074889 N/A N/A 5454 5469AGTTTAGCCTGAAGCA 42 1662 1074921 N/A N/A 5537 5552 CACTCAAGTTACATCC 651663 1074953 N/A N/A 5663 5678 GGGTTTTTGTCATCAG 32 1664 1074985 N/A N/A126504 126519 AATCACCTTTTATTGC 49 1665 1075017 N/A N/A 6099 6114CTTAAAGTGATACACC 19 1666 1075049 N/A N/A 7912 7927 GAAATATTGGTAAGTC 101667 1075081 N/A N/A 10220 10235 GATTACAAAGACAGCC 7 1668 1075113 N/A N/A11804 11819 TATAAATACCAGGTAC 67 1669 1075145 N/A N/A 15306 15321TCCCAAAAGGAGTAGC 58 1670 1075177 N/A N/A 17546 17561 GAAATTACCCGGGAAC 271671 1075209 N/A N/A 22213 22228 CATCAACAATGGTCTA 11 1672 1075241 N/AN/A 25786 25801 GATAATTACTAACTGA 31 1673 1075273 N/A N/A 28145 28160AAATTATGGTCAGGCT 18 1674 1075305 N/A N/A 31621 31636 AAACGAAACACGGGTA 661675 1075337 N/A N/A 32561 32576 GCTTATATCCTGTAAC 48 1676 1075369 N/AN/A 34752 34767 GGAGAATAAGCAATCA 31 1677 1075401 N/A N/A 36720 36735CGATTAAAACACTGGT 3 1678 1075433 N/A N/A 39050 39065 TTAACTAACTAAACTG 1241679 1075465 N/A N/A 41471 41486 GATTTATTGAACTGAG 7 1680 1075497 N/A N/A43504 43519 ATTATATAATGCAGGC 14 1681 1075529 N/A N/A 45618 45633AAATCGAAGGGCAAAC 84 1682 1075561 N/A N/A 47742 47757 GTAAGTAAGGGAACCC 321683 1075593 N/A N/A 49605 49620 CATTAGAGTATGAACT 99 1684 1075625 N/AN/A 51849 51864 AATCTATAACCCTTAT 49 1685 1075657 N/A N/A 53594 53609TAAAAAACGGTTTTTC 84 1686 1075689 N/A N/A 55744 55759 CAACTATACAAGGCAA 41687 1075721 N/A N/A 58637 58652 TTAAATACCTTCTAGC 67 1688 1075753 N/AN/A 60167 60182 CTAGAACCTTTTCCAG 65 1689 1075785 N/A N/A 62704 62719CATTTTATAGGGCCAT 2 1690 1075817 N/A N/A 65591 65606 CCTAAAGAAGTCTTGG 1001691 1075849 N/A N/A 67996 68011 CTAGAACACGCTGATG 55 1692 1075881 N/AN/A 71413 71428 GATTAACTACACCACG 23 1693 1075913 N/A N/A 75193 75208CCCCTATACTTTTTGA 46 1694 1075945 N/A N/A 77600 77615 GTATTAGGAACAGATC 111695 1075977 N/A N/A 80965 80980 GATTAAAAGTCGGGCC 73 1696 1076009 N/AN/A 82387 82402 TAGCGAAAATAACATT 69 1697 1076041 N/A N/A 85661 85676GTTAAAGAGTGGAAAT 47 1698 1076073 N/A N/A 88094 88109 CTTTAAGGTCTAGTTA 471699 1076105 N/A N/A 90641 90656 TACGAAATAGTAACTG 13 1700 1076137 N/AN/A 92375 92390 CACCAACAACCTCATG 45 1701 1076169 N/A N/A 94082 94097CTACTATATCTTTGGG 10 1702 1076201 N/A N/A 96469 96484 CTAAAAAGACAGGGCC 991703 1076233 N/A N/A 98280 98295 CCAATAAAGCAAGTAG 13 1704 1076265 N/AN/A 101306 101321 TATTACCCAATAACCA 9 1705 1076297 N/A N/A 103671 103686TTATAAAGACCCAATG 52 1706 1076329 N/A N/A 107153 107168 AATTATACTGGCTACT14 1707 1076361 N/A N/A 109944 109959 TGGGAAAAGCTACCAC 87 1708 1076393N/A N/A 111591 111606 CTTTACTTACTGGTGG 4 1709 1076425 N/A N/A 114175114190 CGGGAAAATTCTGGAG 32 1710 1076457 N/A N/A 117800 117815GAACTATAATCTTATA 74 1711 1076489 N/A N/A 119885 119900 CAAAATAGGTGAGTCA2 1712 1076521 N/A N/A 122446 122461 ACTAAAGGAGTCATGA 67 1713 1076553N/A N/A 37304 37319 TGGGAATAATTTGGCC 69 1714

TABLE 24Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 1074122139 154 3599 3614 CTGCGAGGCACTCGGA 73 1715 1074154 304 319 3764 3779CCACGGGCCGAGGTGG 100 1716 1074186 410 425 3870 3885 GGGCCGGTTGAGGCGG 741717 1074218 726 741 7160 7175 AGGGCTCCTGCAGTGC 70 1718 1074250 958 973N/A N/A CTGATCGATGTGATTT 6 1719 1074282 1170 1185 79111 79126CGAGGGTCAAGCCTTG 83 1720 1074314 1387 1402 102519 102534ATTGATATTCCGCATT 12 1721 1074346 1534 1549 116723 116738ATCTGAGCTATTGGTC 10 1722 1074378 1708 1723 122733 122748GAAACGGTTCTGCTGT 31 1723 1074410 2041 2056 123066 123081TAGAGGATTAAAGTAT 32 1724 1074442 2351 2366 123376 123391GACCAGTAAATCATGT 21 1725 1074474 2662 2677 123687 123702CCAACCCCCCCACCGA 71 1726 1074506 2807 2822 123832 123847TAATCGAGATTTAAAT 107 1727 1074538 3049 3064 124074 124089ATCCACAGTAATAGCT 31 1728 1074570 3192 3207 124217 124232ATGAACCTACTCACTG 12 1729 1074602 3427 3442 124452 124467TCCAGCTAACTCAAAA 24 1730 1074634 3777 3792 124802 124817GCTGAGGCTTTTCATA 55 1731 1074666 4085 4100 125110 125125CATATACCCAATTTTG 16 1732 1074698 4275 4290 125300 125315TATCAAGGTCCCCCTA 78 1733 1074730 4463 4478 125488 125503TATCACAGTACTGCTA 46 1734 1074762 4630 4645 125655 125670GCTACCCAATACAACC 6 1735 1074794 4779 4794 125804 125819 CAAATCAATGTGCTCC5 1736 1074826 5090 5105 126115 126130 AAATCCACCTGAGCAC 51 1737 10748585246 5261 126271 126286 AACATTGGTACTATAT 23 1738 1074890 N/A N/A 54565471 GAAGTTTAGCCTGAAG 58 1739 1074922 N/A N/A 5542 5557 CTTTCCACTCAAGTTA87 1740 1074954 N/A N/A 5665 5680 CCGGGTTTTTGTCATC 91 1741 1074986 N/AN/A 126511 126526 CTACTGTAATCACCTT 78 1742 1075018 N/A N/A 6100 6115CCTTAAAGTGATACAC 29 1743 1075050 N/A N/A 8047 8062 ACCCAACGGTCATGTT 941744 1075082 N/A N/A 10252 10267 CTTTAGATACAAGAGG 80 1745 1075114 N/AN/A 11805 11820 GTATAAATACCAGGTA 26 1746 1075146 N/A N/A 15570 15585GTATTAAGGGATTTTC 8 1747 1075178 N/A N/A 17552 17567 CTGGAAGAAATTACCC 471748 1075210 N/A N/A 22314 22329 GTATTTTAACCTAAAC 100 1749 1075242 N/AN/A 25790 25805 CAGGGATAATTACTAA 7 1750 1075274 N/A N/A 28203 28218AATAATCCAGCCTAGG 86 1751 1075306 N/A N/A 31622 31637 TAAACGAAACACGGGT 301752 1075338 N/A N/A 32572 32587 CCCAAAAACTAGCTTA 56 1753 1075370 N/AN/A 34931 34946 CTTACGAATCACATAT 32 1754 1075402 N/A N/A 36792 36807GAGCAACACAAGCATA 45 1755 1075434 N/A N/A 39406 39421 GTAAAAGAGGTGCATC 961756 1075466 N/A N/A 41511 41526 TCCAAAAACCATCAGT 28 1757 1075498 N/AN/A 43505 43520 CATTATATAATGCAGG 9 1758 1075530 N/A N/A 45619 45634GAAATCGAAGGGCAAA 30 1759 1075562 N/A N/A 47824 47839 GTATTTATGGCAACAT 151760 1075594 N/A N/A 49676 49691 TGAGAATATTCCTCCC 64 1761 1075626 N/AN/A 51926 51941 CATTAGCCAAAGCTCA 34 1762 1075658 N/A N/A 53595 53610GTAAAAAACGGTTTTT 103 1763 1075690 N/A N/A 55750 55765 CGTTAACAACTATACA33 1764 1075722 N/A N/A 58638 58653 GTTAAATACCTTCTAG 88 1765 1075754 N/AN/A 60230 60245 CTTAAATGGCACAGTT 20 1766 1075786 N/A N/A 62749 62764CTATATTGATTCCAGA 19 1767 1075818 N/A N/A 65659 65674 CATAACTTAGAACCAT 351768 1075850 N/A N/A 68030 68045 CTATAGGTACTTAGAA N.D. 1769 1075882 N/AN/A 71422 71437 GAAAATCCTGATTAAC 73 1770 1075914 N/A N/A 75298 75313ATTTAGGATGCCTTTA 14 1771 1075946 N/A N/A 77683 77698 GCTGAATAAGTAACTT 201772 1075978 N/A N/A 80966 80981 AGATTAAAAGTCGGGC 11 1773 1076010 N/AN/A 82396 82411 TATAAACAATAGCGAA 44 1774 1076042 N/A N/A 85704 85719CTTAAGCAAGAGTCCA 35 1775 1076074 N/A N/A 88162 88177 CTAATTAGCTTTCAGC 921776 1076106 N/A N/A 90642 90657 CTACGAAATAGTAACT 77 1777 1076138 N/AN/A 92409 92424 AGCCAACAATTTTTGG 113 1778 1076170 N/A N/A 94131 94146AGTAAAGAGTACTGTA 16 1779 1076202 N/A N/A 96470 96485 TCTAAAAAGACAGGGC 321780 1076234 N/A N/A 98304 98319 CCTTAATATATCCACA 24 1781 1076266 N/AN/A 101308 101323 ATTATTACCCAATAAC 72 1782 1076298 N/A N/A 103672 103687GTTATAAAGACCCAAT 10 1783 1076330 N/A N/A 107154 107169 GAATTATACTGGCTAC3 1784 1076362 N/A N/A 110095 110110 CCACTAAATAAAGCAG 16 1785 1076394N/A N/A 111629 111644 CCTAAATTAGACTTGA 20 1786 1076426 N/A N/A 114176114191 ACGGGAAAATTCTGGA 9 1787 1076458 N/A N/A 117825 117840CTTAATTAGCCTCAGT 6 1788 1076490 N/A N/A 119886 119901 CCAAAATAGGTGAGTC 21789 1076522 N/A N/A 122448 122463 GCACTAAAGGAGTCAT 35 1790 1076554 N/AN/A 38773 38788 TGGGAATAGTGAATTT 30 1791

TABLE 25Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compound StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′)UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074123140 155 3600 3615 GCTGCGAGGCACTCGG 72 1792 1074155 311 326 3771 3786CCCGGCTCCACGGGCC 87 1793 1074187 439 454 3899 3914 CTGCGAAGGCGGCTGC 471794 1074219 730 745 7164 7179 AGTCAGGGCTCCTGCA 30 1795 1074251 959 974N/A N/A TCTGATCGATGTGATT 7 1796 1074283 1174 1189 79115 79130AAAACGAGGGTCAAGC 12 1797 1074315 1388 1403 102520 102535GATTGATATTCCGCAT 3 1798 1074347 1546 1561 116735 116750 GTTAAGGAAAGGATCT34 1799 1074379 1711 1726 122736 122751 TGGGAAACGGTTCTGC 20 1800 10744112095 2110 123120 123135 TGTGAAAGAGGTCAGC 3 1801 1074443 2354 2369 123379123394 TCAGACCAGTAAATCA 7 1802 1074475 2663 2678 123688 123703ACCAACCCCCCCACCG 72 1803 1074507 2808 2823 123833 123848ATAATCGAGATTTAAA 74 1804 1074539 3051 3066 124076 124091CTATCCACAGTAATAG 62 1805 1074571 3193 3208 124218 124233TATGAACCTACTCACT 37 1806 1074603 3428 3443 124453 124468TTCCAGCTAACTCAAA 17 1807 1074635 3783 3798 124808 124823TCCCAAGCTGAGGCTT 31 1808 1074667 4107 4122 125132 125147CCCAACAACATGCTAT 15 1809 1074699 4276 4291 125301 125316CTATCAAGGTCCCCCT 27 1810 1074731 4467 4482 125492 125507CAGGTATCACAGTACT 19 1811 1074763 4631 4646 125656 125671TGCTACCCAATACAAC 25 1812 1074795 4780 4795 125805 125820CCAAATCAATGTGCTC 4 1813 1074827 5092 5107 126117 126132 TAAAATCCACCTGAGC39 1814 1074859 5248 5263 126273 126288 GTAACATTGGTACTAT 16 1815 1074891N/A N/A 5457 5472 TGAAGTTTAGCCTGAA 31 1816 1074923 N/A N/A 5556 5571GGGCGGTAACTCTTCT 73 1817 1074955 N/A N/A 5666 5681 CCCGGGTTTTTGTCAT 931818 1074987 N/A N/A 4228 4243 GCCGCGGCTCCCGAGC 94 1819 1075019 N/A N/A6185 6200 CATTAGAGTTTGATTA 64 1820 1075051 N/A N/A 8055 8070AATAAACAACCCAACG 56 1821 1075083 N/A N/A 10265 10280 CAACAACACTCCTCTT 541822 1075115 N/A N/A 11890 11905 GTATAGCCTTATTCTT 6 1823 1075147 N/A N/A15583 15598 TATAAACCTTACAGTA 57 1824 1075179 N/A N/A 18169 18184AATTAGCCGGTCCCAG 107 1825 1075211 N/A N/A 22668 22683 AATAAAGGGTCCTAAC91 1826 1075243 N/A N/A 26237 26252 CTTAGTAAGAATTGTC 4 1827 1075275 N/AN/A 28517 28532 CTAGAAAGGCCATGTA 76 1828 1075307 N/A N/A 31624 31639ATTAAACGAAACACGG 28 1829 1075339 N/A N/A 32573 32588 ACCCAAAAACTAGCTT 701830 1075371 N/A N/A 34942 34957 CTGCAAAAGTTCTTAC 90 1831 1075403 N/AN/A 36942 36957 CTTAATCAGGTACTAT 18 1832 1075435 N/A N/A 39516 39531CTTAAACGATAAAGTA 93 1833 1075467 N/A N/A 41522 41537 CATTAATGCCATCCAA 601834 1075499 N/A N/A 43601 43616 GCTAAAAAATGAGTAG 99 1835 1075531 N/AN/A 45685 45700 CTTAATAGTTTAACCT 66 1836 1075563 N/A N/A 47947 47962CCATATAACCAGTTTT 12 1837 1075595 N/A N/A 49869 49884 TATAATACATCTCCCC 501838 1075627 N/A N/A 51985 52000 ATAAGATAGTCGGTTC 19 1839 1075659 N/AN/A 53597 53612 AAGTAAAAAACGGTTT 125 1840 1075691 N/A N/A 55841 55856CGTCAAAATTAACAGA 46 1841 1075723 N/A N/A 58758 58773 TTATCCTATCCCTGGT 321842 1075755 N/A N/A 60231 60246 ACTTAAATGGCACAGT 73 1843 1075787 N/AN/A 62761 62776 CTTAAGGATTGGCTAT 28 1844 1075819 N/A N/A 65672 65687GTATATCCGTTCTCAT 2 1845 1075851 N/A N/A 68466 68481 GCCGAATATGGGAAAA 701846 1075883 N/A N/A 71454 71469 ACTAAAACCATTTGCC 20 1847 1075915 N/AN/A 75299 75314 AATTTAGGATGCCTTT 16 1848 1075947 N/A N/A 78266 78281CTTTATAGGAATAGAG 95 1849 1075979 N/A N/A 81132 81147 CATAATCCACTATGCA 181850 1076011 N/A N/A 82397 82412 ATATAAACAATAGCGA 61 1851 1076043 N/AN/A 85727 85742 CAAAAAGGCTATTGAG 36 1852 1076075 N/A N/A 88209 88224ACACAAGGGTTGCTAA 38 1853 1076107 N/A N/A 90801 90816 CATTACCAACTTCTTC 231854 1076139 N/A N/A 92416 92431 CGAAAAAAGCCAACAA 18 1855 1076171 N/AN/A 94134 94149 ATTAGTAAAGAGTACT 30 1856 1076203 N/A N/A 96576 96591GTTAATACATGGCCAA 29 1857 1076235 N/A N/A 98318 98333 TCAAAATAATCAGCCC 341858 1076267 N/A N/A 101345 101360 ATTTAAGGTGCATAAG 13 1859 1076299 N/AN/A 103673 103688 CGTTATAAAGACCCAA 3 1860 1076331 N/A N/A 107265 107280CATTATTCAGTAGTTG 71 1861 1076363 N/A N/A 110104 110119 CATAAAAGTCCACTAA72 1862 1076395 N/A N/A 111649 111664 GTAACTAACCTAAGGA 34 1863 1076427N/A N/A 114212 114227 CAAATTTACTGATCTC 3 1864 1076459 N/A N/A 117903117918 CTTCAACAAGACAGGT 4 1865 1076491 N/A N/A 119888 119903AGCCAAAATAGGTGAG 12 1866 1076523 N/A N/A 122559 122574 ATTTATATCAGGTCAA5 1867 1076555 N/A N/A 74684 74699 TGGGAATAGTACACAG 19 1868

TABLE 26Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074124141 156 3601 3616 GGCTGCGAGGCACTCG 94 1869 1074156 329 344 3789 3804AGGGCTACGCCCGGAC 96 1870 1074188 440 455 3900 3915 GCTGCGAAGGCGGCTG 1131871 1074220 752 767 7186 7201 AATGAGCTCGAACATG 22 1872 1074252 997 101255492 55507 GGACAGCATGGCCTTC 50 1873 1074284 1175 1190 79116 79131CAAAACGAGGGTCAAG 21 1874 1074316 1389 1404 102521 102536GGATTGATATTCCGCA 33 1875 1074348 1578 1593 120483 120498GTACTCTCATCTCGAG 100 1876 1074380 1714 1729 122739 122754GTCTGGGAAACGGTTC 11 1877 1074412 2096 2111 123121 123136CTGTGAAAGAGGTCAG 55 1878 1074444 2368 2383 123393 123408ACATTTTTGGCTTGTC 3 1879 1074476 2685 2700 123710 123725 TTCCGACAAAACCAAC18 1880 1074508 2818 2833 123843 123858 GAGAGAGCAGATAATC 7 1881 10745403052 3067 124077 124092 ACTATCCACAGTAATA 26 1882 1074572 3194 3209124219 124234 TTATGAACCTACTCAC 17 1883 1074604 3446 3461 124471 124486TTATTAATCTGATCAC 12 1884 1074636 3791 3806 124816 124831ATCTATCTTCCCAAGC 56 1885 1074668 4108 4123 125133 125148TCCCAACAACATGCTA 20 1886 1074700 4320 4335 125345 125360GTAAGACAAGTCTTTA 26 1887 1074732 4468 4483 125493 125508CCAGGTATCACAGTAC 30 1888 1074764 4632 4647 125657 125672ATGCTACCCAATACAA 18 1889 1074796 4782 4797 125807 125822CTCCAAATCAATGTGC 22 1890 1074828 5093 5108 126118 126133ATAAAATCCACCTGAG 58 1891 1074860 5252 5267 126277 126292AAAGGTAACATTGGTA 9 1892 1074892 N/A N/A 5458 5473 CTGAAGTTTAGCCTGA 421893 1074924 N/A N/A 5585 5600 CCTGCAAATAGGAGAG 87 1894 1074956 N/A N/A5667 5682 ACCCGGGTTTTTGTCA 104 1895 1074988 N/A N/A 4324 4339ACCGCGGCGGAGTGGA 94 1896 1075020 N/A N/A 6193 6208 TTAATTAGCATTAGAG 301897 1075052 N/A N/A 8204 8219 ATATATACTTGATCCA 3 1898 1075084 N/A N/A10268 10283 TGACAACAACACTCCT 9 1899 1075116 N/A N/A 11969 11984CTTAACATTTAATGGC 15 1900 1075148 N/A N/A 16000 16015 CGGAAAAAACACCTAG 661901 1075180 N/A N/A 18759 18774 TATTACTACAACCATA 56 1902 1075212 N/AN/A 22669 22684 CAATAAAGGGTCCTAA 76 1903 1075244 N/A N/A 26292 26307ACCCAAAAATTCTGTG 76 1904 1075276 N/A N/A 28647 28662 GACCAATACAATGGGA 781905 1075308 N/A N/A 31625 31640 AATTAAACGAAACACG 97 1906 1075340 N/AN/A 32580 32595 CCCGAACACCCAAAAA 103 1907 1075372 N/A N/A 34997 35012ATATATAGACTTGAGA 27 1908 1075404 N/A N/A 37268 37283 ATATAACCTGAACTAA102 1909 1075436 N/A N/A 39517 39532 CCTTAAACGATAAAGT 89 1910 1075468N/A N/A 41570 41585 CACCAATACTGAGTAT 91 1911 1075500 N/A N/A 43668 43683TAAATTAAGCCAACAC 26 1912 1075532 N/A N/A 45686 45701 ACTTAATAGTTTAACC121 1913 1075564 N/A N/A 48028 48043 ATATAACAGGCCACCA 81 1914 1075596N/A N/A 49870 49885 ATATAATACATCTCCC 91 1915 1075628 N/A N/A 52040 52055CCGCAAAATATTAATT 118 1916 1075660 N/A N/A 53599 53614 CAAAGTAAAAAACGGT72 1917 1075692 N/A N/A 55999 56014 TAAGAACACCATAGCA 11 1918 1075724 N/AN/A 58769 58784 CTATCTGTCAGTTATC 44 1919 1075756 N/A N/A 60243 60258ATTTACCCTGCCACTT 49 1920 1075788 N/A N/A 62762 62777 TCTTAAGGATTGGCTA 151921 1075820 N/A N/A 65896 65911 TCTGAACGGGCTGTTG 27 1922 1075852 N/AN/A 68471 68486 GATAAGCCGAATATGG 58 1923 1075884 N/A N/A 71468 71483ATTAGTAATGACTAAC 116 1924 1075916 N/A N/A 75300 75315 CAATTTAGGATGCCTT 61925 1075948 N/A N/A 78306 78321 GGACTAAAGAATACAG 31 1926 1075980 N/AN/A 81219 81234 CAATATCCTACACCAT 43 1927 1076012 N/A N/A 82398 82413AATATAAACAATAGCG 34 1928 1076044 N/A N/A 85729 85744 ATCAAAAAGGCTATTG 731929 1076076 N/A N/A 88372 88387 TATCAATACTTTAGTC 57 1930 1076108 N/AN/A 90863 90878 AAACAAAACCGGCTTT 116 1931 1076140 N/A N/A 92417 92432ACGAAAAAAGCCAACA 28 1932 1076172 N/A N/A 94135 94150 TATTAGTAAAGAGTAC 981933 1076204 N/A N/A 96620 96635 GATAATGAATCCTTGT 11 1934 1076236 N/AN/A 98440 98455 GGAGAACCTTATTTAT 51 1935 1076268 N/A N/A 101514 101529GTACAATAATGCTTCC 10 1936 1076300 N/A N/A 103687 103702 AAAAAATGGCTTCACG22 1937 1076332 N/A N/A 107285 107300 TATAAGGAATGGCAAC 107 1938 1076364N/A N/A 110105 110120 CCATAAAAGTCCACTA 30 1939 1076396 N/A N/A 111672111687 CTATATTTGAGCCATG 2 1940 1076428 N/A N/A 114406 114421ATTAAAAAGAAGCACG 53 1941 1076460 N/A N/A 117914 117929 TAATATAGCCCCTTCA7 1942 1076492 N/A N/A 120180 120195 AAAAGATACCCCCAGT 47 1943 1076524N/A N/A 122560 122575 AATTTATATCAGGTCA 6 1944 1076556 N/A N/A 116991117006 GTATAGGCAGAAGCAA 9 1945

TABLE 27Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 1074125160 175 3620 3635 GCGGCTGCGCCTCGGG 94 1946 1074157 333 348 3793 3808AGCGAGGGCTACGCCC 103 1947 1074189 441 456 3901 3916 GGCTGCGAAGGCGGCT 961948 1074221 753 768 7187 7202 GAATGAGCTCGAACAT 6 1949 1074253 1001 101655496 55511 TCTGGGACAGCATGGC 11 1950 1074285 1176 1191 N/A N/AGCAAAACGAGGGTCAA 17 1951 1074317 1406 1421 102538 102553GAGAATTTGCTGTGCT 12 1952 1074349 1580 1595 120485 120500CTGTACTCTCATCTCG 30 1953 1074381 1715 1730 122740 122755AGTCTGGGAAACGGTT 16 1954 1074413 2097 2112 123122 123137ACTGTGAAAGAGGTCA 4 1955 1074445 2471 2486 123496 123511 TGATAGCACTAGGAGG6 1956 1074477 2686 2701 123711 123726 GTTCCGACAAAACCAA 10 1957 10745092850 2865 123875 123890 TGTTATGTTTGGGTGT 5 1958 1074541 3053 3068 124078124093 CACTATCCACAGTAAT 23 1959 1074573 3195 3210 124220 124235ATTATGAACCTACTCA 14 1960 1074605 3464 3479 124489 124504TCAACTACCAATATAC 20 1961 1074637 3792 3807 124817 124832AATCTATCTTCCCAAG 36 1962 1074669 4109 4124 125134 125149ATCCCAACAACATGCT 13 1963 1074701 4322 4337 125347 125362GTGTAAGACAAGTCTT 17 1964 1074733 4469 4484 125494 125509GCCAGGTATCACAGTA 47 1965 1074765 4634 4649 125659 125674CAATGCTACCCAATAC 34 1966 1074797 4783 4798 125808 125823ACTCCAAATCAATGTG 31 1967 1074829 5095 5110 126120 126135GGATAAAATCCACCTG 92 1968 1074861 5279 5294 126304 126319TGCTCTTACATCTAAA 23 1969 1074893 N/A N/A 5459 5474 GCTGAAGTTTAGCCTG 781970 1074925 N/A N/A 5586 5601 GCCTGCAAATAGGAGA 94 1971 1074957 N/A N/A5668 5683 AACCCGGGTTTTTGTC 102 1972 1074989 N/A N/A 4423 4438GAGGGAAAGCACGCCC 105 1973 1075021 N/A N/A 6245 6260 TTACAACCTAGATTTG 681974 1075053 N/A N/A 8205 8220 AATATATACTTGATCC 4 1975 1075085 N/A N/A10318 10333 TGCGGAAACAAGTGTA 11 1976 1075117 N/A N/A 12081 12096CCTCAATAGCAAGACA 48 1977 1075149 N/A N/A 16001 16016 GCGGAAAAAACACCTA 501978 1075181 N/A N/A 18762 18777 TTATATTACTACAACC 15 1979 1075213 N/AN/A 22670 22685 ACAATAAAGGGTCCTA 33 1980 1075245 N/A N/A 26692 26707CCTAATATGCTATTGT 34 1981 1075277 N/A N/A 28762 28777 TTATAAGAACTGTGGC 131982 1075309 N/A N/A 31626 31641 TAATTAAACGAAACAC 110 1983 1075341 N/AN/A 32592 32607 GCTGAACAATCTCCCG 31 1984 1075373 N/A N/A 34998 35013TATATATAGACTTGAG 13 1985 1075405 N/A N/A 37270 37285 CTATATAACCTGAACT 841986 1075437 N/A N/A 39572 39587 TATTAGTACGAGCTAC 85 1987 1075469 N/AN/A 41723 41738 TGATATAATGACCAAG 25 1988 1075501 N/A N/A 43670 43685CATAAATTAAGCCAAC 67 1989 1075533 N/A N/A 45730 45745 GATTACTCAGCTATGT 651990 1075565 N/A N/A 48029 48044 TATATAACAGGCCACC 52 1991 1075597 N/AN/A 49954 49969 ATTAACATTTGCCCGC 47 1992 1075629 N/A N/A 52041 52056GCCGCAAAATATTAAT 100 1993 1075661 N/A N/A 53794 53809 GAATAGGATACAAGCA74 1994 1075693 N/A N/A 56014 56029 CATTAAAAGTTGGGTT 36 1995 1075725 N/AN/A 58772 58787 ATCCTATCTGTCAGTT 18 1996 1075757 N/A N/A 60324 60339CTTAATACATTATTCC 2 1997 1075789 N/A N/A 62993 63008 AATTACAAGCTAATGC 791998 1075821 N/A N/A 66155 66170 CTTAACTTCCCACTCG 22 1999 1075853 N/AN/A 68653 68668 GAGCGATAAGCTGTAT 72 2000 1075885 N/A N/A 71469 71484CATTAGTAATGACTAA 112 2001 1075917 N/A N/A 75472 75487 AGCAAAAAGTGATATG55 2002 1075949 N/A N/A 78635 78650 TAGGAACACCAAGGTT 48 2003 1075981 N/AN/A 81222 81237 AAGCAATATCCTACAC 40 2004 1076013 N/A N/A 82644 82659GTTTAATACCTCTGAC 76 2005 1076045 N/A N/A 85776 85791 GTGCAATAAATAGTTC 112006 1076077 N/A N/A 88420 88435 GGATTAAAGTTTTCAC 5 2007 1076109 N/A N/A91026 91041 CTTAAATGACCAATTC 23 2008 1076141 N/A N/A 92418 92433TACGAAAAAAGCCAAC 29 2009 1076173 N/A N/A 94244 94259 CAATATATCCTGAGAT 912010 1076205 N/A N/A 96783 96798 TAGTATAATTCATGAC 51 2011 1076237 N/AN/A 98456 98471 ACTAAAGGACAAAGGT 109 2012 1076269 N/A N/A 101560 101575GACGAAAAATATTCTT 28 2013 1076301 N/A N/A 104195 104210 GTATAAGACCTTGGGA34 2014 1076333 N/A N/A 107286 107301 CTATAAGGAATGGCAA 97 2015 1076365N/A N/A 110141 110156 TAAGAAGGGCCAATGG 15 2016 1076397 N/A N/A 111675111690 AACCTATATTTGAGCC 4 2017 1076429 N/A N/A 114456 114471CATTACAAGCATAGGC 26 2018 1076461 N/A N/A 117917 117932 GATTAATATAGCCCCT3 2019 1076493 N/A N/A 120197 120212 TGACAATAAGGGACAA 34 2020 1076525N/A N/A 122561 122576 GAATTTATATCAGGTC 3 2021 1076557 N/A N/A 5541155426 AACAAATACCAGGTTC 111 2022

TABLE 28Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 1074126163 178 3623 3638 CTGGCGGCTGCGCCTC 111 2023 1074158 334 349 3794 3809GAGCGAGGGCTACGCC 72 2024 1074190 463 478 3923 3938 CGGCGGGCCCTGCCCC 1142025 1074222 755 770 7189 7204 AGGAATGAGCTCGAAC 5 2026 1074254 1002 101755497 55512 ATCTGGGACAGCATGG 13 2027 1074286 1193 1208 98895 98910TGATTCTCTGGTTCAT 32 2028 1074318 1407 1422 102539 102554GGAGAATTTGCTGTGC 4 2029 1074350 1591 1606 120496 120511 TAGTCCACTGTCTGTA14 2030 1074382 1719 1734 122744 122759 AGGTAGTCTGGGAAAC 8 2031 10744142098 2113 123123 123138 AACTGTGAAAGAGGTC 6 2032 1074446 2472 2487 123497123512 ATGATAGCACTAGGAG 3 2033 1074478 2691 2706 123716 123731CCTAGGTTCCGACAAA 69 2034 1074510 2878 2893 123903 123918ATACATTCCACTACCA 10 2035 1074542 3056 3071 124081 124096AGGCACTATCCACAGT 21 2036 1074574 3196 3211 124221 124236CATTATGAACCTACTC 17 2037 1074606 3500 3515 124525 124540GGTATAATCATGATTA 4 2038 1074638 3816 3831 124841 124856 AGATTTTGTAATTGGG2 2039 1074670 4141 4156 125166 125181 AAGTAGCTTTGATCTT 49 2040 10747024323 4338 125348 125363 GGTGTAAGACAAGTCT 16 2041 1074734 4470 4485125495 125510 TGCCAGGTATCACAGT 51 2042 1074766 4638 4653 125663 125678ATCCCAATGCTACCCA 8 2043 1074798 4800 4815 125825 125840 GCTTTGGAAGATCTGA4 2044 1074830 5097 5112 126122 126137 GAGGATAAAATCCACC 89 2045 10748625287 5302 126312 126327 TATGAGCATGCTCTTA 56 2046 1074894 N/A N/A 54605475 TGCTGAAGTTTAGCCT 79 2047 1074926 N/A N/A 5592 5607 CAACAGGCCTGCAAAT111 2048 1074958 N/A N/A 5669 5684 TAACCCGGGTTTTTGT 107 2049 1074990 N/AN/A 4687 4702 GCCGCAAAGGAAAGGG 108 2050 1075022 N/A N/A 6247 6262ATTTACAACCTAGATT 91 2051 1075054 N/A N/A 8206 8221 CAATATATACTTGATC 482052 1075086 N/A N/A 10392 10407 AGTTATAGACTTTGTA 25 2053 1075118 N/AN/A 12281 12296 CTATTTACTCTGTCAC 4 2054 1075150 N/A N/A 16002 16017AGCGGAAAAAACACCT 35 2055 1075182 N/A N/A 18766 18781 GATATTATATTACTAC 612056 1075214 N/A N/A 22671 22686 AACAATAAAGGGTCCT 45 2057 1075246 N/AN/A 26760 26775 GATAACTAGTAACCGT 6 2058 1075278 N/A N/A 28866 28881TATACTAACATTCACG 48 2059 1075310 N/A N/A 31627 31642 GTAATTAAACGAAACA 842060 1075342 N/A N/A 32636 32651 ACTAAAAGGGAGTAGG 87 2061 1075374 N/AN/A 35122 35137 GAAAATACTCCTCCTA 27 2062 1075406 N/A N/A 37271 37286ACTATATAACCTGAAC 99 2063 1075438 N/A N/A 39657 39672 CATATTAGAGTTGAGG 222064 1075470 N/A N/A 41860 41875 GCCAATAAGTTATCAA 50 2065 1075502 N/AN/A 44236 44251 CTTAACATGATTCTAG 61 2066 1075534 N/A N/A 45787 45802ACCCAAGGACAGCACA 53 2067 1075566 N/A N/A 48030 48045 ATATATAACAGGCCAC 502068 1075598 N/A N/A 49955 49970 AATTAACATTTGCCCG 62 2069 1075630 N/AN/A 52052 52067 TATAACCAAATGCCGC 60 2070 1075662 N/A N/A 53888 53903AAGGGATACAAGTGTT 78 2071 1075694 N/A N/A 56015 56030 ACATTAAAAGTTGGGT 112072 1075726 N/A N/A 58776 58791 AGTTATCCTATCTGTC 14 2073 1075758 N/AN/A 60403 60418 GTAATTTAATAGACTA 73 2074 1075790 N/A N/A 63026 63041TCAGAAGAACTCCCAT 14 2075 1075822 N/A N/A 66205 66220 CTTAGTAATTGCCCAT 352076 1075854 N/A N/A 68837 68852 CTTATAATAGAGCTAA 52 2077 1075886 N/AN/A 71526 71541 CATAACACTGAAGGTG 60 2078 1075918 N/A N/A 75510 75525CTTAAACTAACTGTTG 82 2079 1075950 N/A N/A 78649 78664 TGACAATACCTTCCTA 302080 1075982 N/A N/A 81227 81242 CATGAAAGCAATATCC 23 2081 1076014 N/AN/A 82658 82673 AATCAACCTATGAGGT 98 2082 1076046 N/A N/A 85784 85799CTTAAATGGTGCAATA 28 2083 1076078 N/A N/A 89187 89202 CTTTAGCCTCTATACC 232084 1076110 N/A N/A 91091 91106 CTTTACCTAAATGTTG 53 2085 1076142 N/AN/A 92419 92434 ATACGAAAAAAGCCAA 38 2086 1076174 N/A N/A 94299 94314GATATATGGTAGCATA 3 2087 1076206 N/A N/A 96835 96850 CAATAAACTTACCCTT 552088 1076238 N/A N/A 98513 98528 GATGAATAGCTAAGAA 30 2089 1076270 N/AN/A 101571 101586 TAACAATAGTAGACGA 28 2090 1076302 N/A N/A 104337 104352AATAAGCCTCACCTTT 74 2091 1076334 N/A N/A 107288 107303 ACCTATAAGGAATGGC108 2092 1076366 N/A N/A 110167 110182 ATTTACATGAGAGGAG 4 2093 1076398N/A N/A 111707 111722 CTTGAAGGGCTATGGA 62 2094 1076430 N/A N/A 114752114767 CGTTATAAGATGTGCT 4 2095 1076462 N/A N/A 117971 117986TCAGAAGGATATGCAG 6 2096 1076494 N/A N/A 120254 120269 CTAATTGAAGCTGGCA 32097 1076526 N/A N/A 102684 102699 GTAGAAAGATGGCTCA 3 2098 1076558 N/AN/A 82852 82867 GCCAAATATTTAACTC 30 2099

TABLE 29Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 1074127171 186 3631 3646 CCACTGGTCTGGCGGC 57 2100 1074159 335 350 3795 3810CGAGCGAGGGCTACGC 77 2101 1074191 464 479 3924 3939 ACGGCGGGCCCTGCCC 802102 1074223 786 801 7220 7235 GAAACAGCTCCCAACT 48 2103 1074255 10041019 55499 55514 TCATCTGGGACAGCAT 16 2104 1074287 1195 1210 98897 98912ACTGATTCTCTGGTTC 11 2105 1074319 1425 1440 N/A N/A GCTAACTCCTGACATT 472106 1074351 1596 1611 120501 120516 ATGCTTAGTCCACTGT 7 2107 10743831722 1737 122747 122762 TCAAGGTAGTCTGGGA 40 2108 1074415 2101 2116123126 123141 GCCAACTGTGAAAGAG 10 2109 1074447 2473 2488 123498 123513AATGATAGCACTAGGA 4 2110 1074479 2697 2712 123722 123737 CATTTGCCTAGGTTCC2 2111 1074511 2879 2894 123904 123919 GATACATTCCACTACC 9 2112 10745433059 3074 124084 124099 CCTAGGCACTATCCAC 57 2113 1074575 3197 3212124222 124237 ACATTATGAACCTACT 14 2114 1074607 3502 3517 124527 124542AAGGTATAATCATGAT 4 2115 1074639 3817 3832 124842 124857 TAGATTTTGTAATTGG3 2116 1074671 4142 4157 125167 125182 CAAGTAGCTTTGATCT 8 2117 10747034324 4339 125349 125364 CGGTGTAAGACAAGTC 16 2118 1074735 4483 4498125508 125523 GATCAAAGCACTGTGC 117 2119 1074767 4640 4655 125665 125680TTATCCCAATGCTACC 12 2120 1074799 4801 4816 125826 125841TGCTTTGGAAGATCTG 8 2121 1074831 5098 5113 126123 126138 CGAGGATAAAATCCAC35 2122 1074863 5288 5303 126313 126328 ATATGAGCATGCTCTT 41 2123 1074895N/A N/A 5465 5480 TCCTATGCTGAAGTTT 60 2124 1074927 N/A N/A 5594 5609TACAACAGGCCTGCAA 74 2125 1074959 N/A N/A 5670 5685 TTAACCCGGGTTTTTG 1282126 1074991 N/A N/A 4727 4742 AATTATTTGACTCCCC 60 2127 1075023 N/A N/A6249 6264 GTATTTACAACCTAGA 18 2128 1075055 N/A N/A 8271 8286CTATTAAGTGAGCTTT 4 2129 1075087 N/A N/A 10400 10415 TCTCAATAAGTTATAG 392130 1075119 N/A N/A 12305 12320 AGGGAATATGTTAATC 8 2131 1075151 N/A N/A16014 16029 TTTAAAAGTACCAGCG 60 2132 1075183 N/A N/A 18905 18920ATTACTAAGACAGTGG 15 2133 1075215 N/A N/A 22672 22687 AAACAATAAAGGGTCC 442134 1075247 N/A N/A 26764 26779 CTAAGATAACTAGTAA 101 2135 1075279 N/AN/A 28867 28882 CTATACTAACATTCAC 52 2136 1075311 N/A N/A 31628 31643AGTAATTAAACGAAAC 100 2137 1075343 N/A N/A 32637 32652 AACTAAAAGGGAGTAG89 2138 1075375 N/A N/A 35237 35252 CTAAATATCAACTCCC 35 2139 1075407 N/AN/A 37273 37288 GAACTATATAACCTGA 32 2140 1075439 N/A N/A 39815 39830AATTAGAGATATGGAC 77 2141 1075471 N/A N/A 41861 41876 AGCCAATAAGTTATCA 552142 1075503 N/A N/A 44248 44263 GCTGAAAAAGGGCTTA 66 2143 1075535 N/AN/A 45791 45806 AATTACCCAAGGACAG 53 2144 1075567 N/A N/A 48031 48046GATATATAACAGGCCA 65 2145 1075599 N/A N/A 49979 49994 ACCCTATAGCTTTAGG 902146 1075631 N/A N/A 52055 52070 CCCTATAACCAAATGC 104 2147 1075663 N/AN/A 53926 53941 CTAAATAGGTGGTTAT 80 2148 1075695 N/A N/A 56025 56040GAATAACACCACATTA 30 2149 1075727 N/A N/A 58798 58813 TTATCGGAGGCTTCGC 312150 1075759 N/A N/A 60742 60757 CCTTATAAATTATGAC 44 2151 1075791 N/AN/A 63059 63074 CTTTATCAGCCATCAC 10 2152 1075823 N/A N/A 66222 66237TATTAGAGGTTCCAGG 30 2153 1075855 N/A N/A 68937 68952 GATTTTTAGGCAGACG 72154 1075887 N/A N/A 71602 71617 TATTACTTGATTGACA 10 2155 1075919 N/AN/A 75511 75526 TCTTAAACTAACTGTT 78 2156 1075951 N/A N/A 78699 78714CACGGAAGAGCTTGCA 34 2157 1075983 N/A N/A 81249 81264 ATCGAAAAGCAAACTC 52158 1076015 N/A N/A 82981 82996 ATTTAGTTGGTTGTTA 8 2159 1076047 N/A N/A85785 85800 ACTTAAATGGTGCAAT 34 2160 1076079 N/A N/A 89467 89482AAGCAATATATGGCCT 37 2161 1076111 N/A N/A 91203 91218 AATTAGTTAGGATATC 672162 1076143 N/A N/A 92420 92435 GATACGAAAAAAGCCA 8 2163 1076175 N/A N/A94392 94407 CAATAGGTAACAGGTA 15 2164 1076207 N/A N/A 96838 96853AGTCAATAAACTTACC 58 2165 1076239 N/A N/A 98583 98598 GTTTAAAAAAAACGGG 752166 1076271 N/A N/A 101685 101700 CGGCAACAACAAAATG 18 2167 1076303 N/AN/A 104339 104354 CTAATAAGCCTCACCT 34 2168 1076335 N/A N/A 107289 107304CACCTATAAGGAATGG 80 2169 1076367 N/A N/A 110169 110184 CTATTTACATGAGAGG3 2170 1076399 N/A N/A 111771 111786 GATAACTTAGAGATGT 4 2171 1076431 N/AN/A 114853 114868 CACCAATAGAACATAT 31 2172 1076463 N/A N/A 118082 118097GATTAGTAACACTGAT 38 2173 1076495 N/A N/A 120353 120368 GATTAGTGAAAATTCC30 2174 1076527 N/A N/A 117218 117233 GCACAACCTTACATTT 6 2175 1076559N/A N/A 111532 111547 AACAAATATAGTTAGC 74 2176

TABLE 30Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074128173 188 3633 3648 CTCCACTGGTCTGGCG 76 2177 1074160 336 351 3796 3811GCGAGCGAGGGCTACG 86 2178 1074192 465 480 3925 3940 GACGGCGGGCCCTGCC 1082179 1074224 821 836 7255 7270 CAGAGACTACTCCAGT 16 2180 1074256 10331048 55528 55543 CACTGGTGGACTGGTG 64 2181 1074288 1196 1211 98898 98913GACTGATTCTCTGGTT 48 2182 1074320 1426 1441 N/A N/A GGCTAACTCCTGACAT 802183 1074352 1597 1612 120502 120517 CATGCTTAGTCCACTG 69 2184 10743841723 1738 122748 122763 TTCAAGGTAGTCTGGG 35 2185 1074416 2108 2123123133 123148 CTTTAGAGCCAACTGT 9 2186 1074448 2474 2489 123499 123514TAATGATAGCACTAGG 3 2187 1074480 2698 2713 123723 123738 TCATTTGCCTAGGTTC3 2188 1074512 2880 2895 123905 123920 GGATACATTCCACTAC 64 2189 10745443063 3078 124088 124103 CTCCCCTAGGCACTAT 34 2190 1074576 3201 3216124226 124241 ATGCACATTATGAACC 7 2191 1074608 3529 3544 124554 124569GTTACATCATCTCTTC 5 2192 1074640 3828 3843 124853 124868 GCCAAAATACTTAGAT26 2193 1074672 4143 4158 125168 125183 CCAAGTAGCTTTGATC 6 2194 10747044326 4341 125351 125366 CACGGTGTAAGACAAG 16 2195 1074736 4504 4519125529 125544 TCAGTACAGAGGGCAT 4 2196 1074768 4641 4656 125666 125681CTTATCCCAATGCTAC 11 2197 1074800 4808 4823 125833 125848CAAATAGTGCTTTGGA 6 2198 1074832 5099 5114 126124 126139 GCGAGGATAAAATCCA17 2199 1074864 5289 5304 126314 126329 CATATGAGCATGCTCT 47 2200 1074896N/A N/A 5472 5487 GCAAAGTTCCTATGCT 99 2201 1074928 N/A N/A 5595 5610ATACAACAGGCCTGCA 83 2202 1074960 N/A N/A 5671 5686 CTTAACCCGGGTTTTT 812203 1074992 N/A N/A 4728 4743 CAATTATTTGACTCCC 63 2204 1075024 N/A N/A6368 6383 ACTGAACAAGTATCTT 32 2205 1075056 N/A N/A 8297 8312CTTTATTATCTCAACC 21 2206 1075088 N/A N/A 10433 10448 ATTTATAGTCAGGTTC 22207 1075120 N/A N/A 12519 12534 AATTAGCCTACCACCT 42 2208 1075152 N/AN/A 16101 16116 TATAATGGGAGGATTA 99 2209 1075184 N/A N/A 18998 19013CAAGAACACTGGTATT 67 2210 1075216 N/A N/A 23247 23262 TATTTTACACGAACTA 552211 1075248 N/A N/A 26930 26945 GTACAAAAAGCGGTCG 64 2212 1075280 N/AN/A 28870 28885 GAACTATACTAACATT 57 2213 1075312 N/A N/A 31662 31677TTAATTGAACTCAGGG 37 2214 1075344 N/A N/A 32638 32653 TAACTAAAAGGGAGTA 912215 1075376 N/A N/A 35238 35253 CCTAAATATCAACTCC 72 2216 1075408 N/AN/A 37387 37402 CTAAAATGGCATAAGG 23 2217 1075440 N/A N/A 39843 39858AAATTATTAGTTGTCG 28 2218 1075472 N/A N/A 41890 41905 GATTATAGTTAAACAG 922219 1075504 N/A N/A 44291 44306 CTTAAATGAGAGAACC 71 2220 1075536 N/AN/A 45793 45808 TTAATTACCCAAGGAC 55 2221 1075568 N/A N/A 48108 48123TTATTTAAGTTGGGAG 23 2222 1075600 N/A N/A 49991 50006 CACTATAATCTGACCC 682223 1075632 N/A N/A 52056 52071 TCCCTATAACCAAATG 95 2224 1075664 N/AN/A 53927 53942 GCTAAATAGGTGGTTA 87 2225 1075696 N/A N/A 56066 56081TTACAAAAGTTACTGC 28 2226 1075728 N/A N/A 58800 58815 CTTTATCGGAGGCTTC 152227 1075760 N/A N/A 61106 61121 GAGAAAAACTACGGAT 39 2228 1075792 N/AN/A 63072 63087 GATTAGAAAGTGCCTT 6 2229 1075824 N/A N/A 66223 66238GTATTAGAGGTTCCAG 3 2230 1075856 N/A N/A 68965 68980 CCTAATCAAGTTCTGC 402231 1075888 N/A N/A 71648 71663 ACTTAAACTTGAGGGA 22 2232 1075920 N/AN/A 75749 75764 AAAGAAAGCTGCGCAC 108 2233 1075952 N/A N/A 78848 78863CTATATACCTGCTTCT 41 2234 1075984 N/A N/A 81250 81265 TATCGAAAAGCAAACT 442235 1076016 N/A N/A 83002 83017 TAATAGGATGGATTCT 8 2236 1076048 N/A N/A85859 85874 GATTAAAGGCTGGAAG 32 2237 1076080 N/A N/A 89574 89589CATTAGCAGTTCACTA 55 2238 1076112 N/A N/A 91226 91241 ATTCAAAACCACGGAA 982239 1076144 N/A N/A 92435 92450 TTTTATAGGGCAATGG 7 2240 1076176 N/A N/A94395 94410 CTCCAATAGGTAACAG 43 2241 1076208 N/A N/A 97037 97052GAGGAATATTACAGAC 15 2242 1076240 N/A N/A 98611 98626 ATTAAAAGCAAGGTGC 562243 1076272 N/A N/A 101702 101717 TTAGAACAACTACTAC 53 2244 1076304 N/AN/A 104340 104355 ACTAATAAGCCTCACC 30 2245 1076336 N/A N/A 107295 107310CATTACCACCTATAAG 31 2246 1076368 N/A N/A 110251 110266 CATTTTATGTAAGGCC15 2247 1076400 N/A N/A 111869 111884 GTTAAAAGCCGTGAAA 10 2248 1076432N/A N/A 114880 114895 CATTAGTATTCACTGT 18 2249 1076464 N/A N/A 118102118117 CATATACAATTCTGCC 2 2250 1076496 N/A N/A 120437 120452GTTAAAGACCAACACA 81 2251 1076528 N/A N/A 16102 16117 TTATAATGGGAGGATT 862252 1076560 N/A N/A 113259 113274 TCCAAATATGGCATAC 10 2253

TABLE 31Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074129178 193 3638 3653 CCCGGCTCCACTGGTC 77 2254 1074161 337 352 3797 3812GGCGAGCGAGGGCTAC 98 2255 1074193 471 486 3931 3946 GGTCCGGACGGCGGGC 742256 1074225 822 837 7256 7271 CCAGAGACTACTCCAG 11 2257 1074257 10341049 55529 55544 GCACTGGTGGACTGGT 29 2258 1074289 1197 1212 98899 98914TGACTGATTCTCTGGT 13 2259 1074321 1427 1442 N/A N/A GGGCTAACTCCTGACA 732260 1074353 1612 1627 120517 120532 GACACTGTAGCTGCTC 17 2261 10743851724 1739 122749 122764 CTTCAAGGTAGTCTGG 17 2262 1074417 2109 2124123134 123149 TCTTTAGAGCCAACTG 2 2263 1074449 2475 2490 123500 123515CTAATGATAGCACTAG 36 2264 1074481 2705 2720 123730 123745AATATGGTCATTTGCC 14 2265 1074513 2881 2896 123906 123921AGGATACATTCCACTA 47 2266 1074545 3064 3079 124089 124104ACTCCCCTAGGCACTA 18 2267 1074577 3211 3226 124236 124251TATTTCTGTCATGCAC 3 2268 1074609 3532 3547 124557 124572 CTAGTTACATCATCTC8 2269 1074641 3829 3844 124854 124869 GGCCAAAATACTTAGA 107 2270 10746734154 4169 125179 125194 AGGCACTCCTTCCAAG 43 2271 1074705 4327 4342125352 125367 GCACGGTGTAAGACAA 20 2272 1074737 4510 4525 125535 125550TTCAGGTCAGTACAGA 7 2273 1074769 4642 4657 125667 125682 TCTTATCCCAATGCTA12 2274 1074801 4809 4824 125834 125849 ACAAATAGTGCTTTGG 8 2275 10748335100 5115 126125 126140 TGCGAGGATAAAATCC 17 2276 1074865 5290 5305126315 126330 ACATATGAGCATGCTC 46 2277 1074897 N/A N/A 5473 5488GGCAAAGTTCCTATGC 76 2278 1074929 N/A N/A 5596 5611 TATACAACAGGCCTGC 792279 1074961 N/A N/A 5676 5691 TCCTCCTTAACCCGGG 93 2280 1074993 N/A N/A4755 4770 TCTAATCAACACTGGA 65 2281 1075025 N/A N/A 6468 6483ACTTAAGAACTCACAC 58 2282 1075057 N/A N/A 8351 8366 CCTTAGGAGTAGACTG 142283 1075089 N/A N/A 10434 10449 CATTTATAGTCAGGTT 2 2284 1075121 N/A N/A12521 12536 AAAATTAGCCTACCAC 40 2285 1075153 N/A N/A 16103 16118ATTATAATGGGAGGAT 38 2286 1075185 N/A N/A 19001 19016 GCCCAAGAACACTGGT 782287 1075217 N/A N/A 23248 23263 TTATTTTACACGAACT 71 2288 1075249 N/AN/A 27029 27044 ATTACGATTAGATCAG 5 2289 1075281 N/A N/A 29105 29120CAGCAAAAGTACCATG 36 2290 1075313 N/A N/A 31663 31678 CTTAATTGAACTCAGG 282291 1075345 N/A N/A 32639 32654 GTAACTAAAAGGGAGT 29 2292 1075377 N/AN/A 35267 35282 CTAGAAAGGTTGGCCC 108 2293 1075409 N/A N/A 37405 37420CTTTAAATAGCAGAGG 22 2294 1075441 N/A N/A 40002 40017 GAATTAAAGCAGTGCC 242295 1075473 N/A N/A 41930 41945 AGTTATAACTGTACTA 89 2296 1075505 N/AN/A 44322 44337 GCTAAATTACAGAGGT 18 2297 1075537 N/A N/A 45795 45810CTTTAATTACCCAAGG 82 2298 1075569 N/A N/A 48125 48140 GTAGAAAGGCATTAGA 452299 1075601 N/A N/A 49992 50007 ACACTATAATCTGACC 50 2300 1075633 N/AN/A 52118 52133 CTATATTGGCTCCTAG 82 2301 1075665 N/A N/A 53953 53968ATTTAGTTGTGCACAG 87 2302 1075697 N/A N/A 56110 56125 AATAATCCATGCTTGC 162303 1075729 N/A N/A 58853 58868 TATTTAAAAATAGCGC 88 2304 1075761 N/AN/A 61107 61122 GGAGAAAAACTACGGA 13 2305 1075793 N/A N/A 63128 63143CATTAGTTGCCCTGAC 31 2306 1075825 N/A N/A 66353 66368 CCCCTAAAGAAGATTT 442307 1075857 N/A N/A 68976 68991 CTTAAACAATCCCTAA 69 2308 1075889 N/AN/A 72204 72219 ATTAAAAGTAGGCCCT 71 2309 1075921 N/A N/A 75750 75765GAAAGAAAGCTGCGCA 93 2310 1075953 N/A N/A 78851 78866 AACCTATATACCTGCT 362311 1075985 N/A N/A 81251 81266 ATATCGAAAAGCAAAC 82 2312 1076017 N/AN/A 83003 83018 CTAATAGGATGGATTC 5 2313 1076049 N/A N/A 85860 85875AGATTAAAGGCTGGAA 4 2314 1076081 N/A N/A 89730 89745 GATAATTCACCCTTGT 152315 1076113 N/A N/A 91298 91313 TGACAATAGCCAATGC 16 2316 1076145 N/AN/A 92457 92472 CCTTATAGGTTATAGT 41 2317 1076177 N/A N/A 94422 94437CTTTATTTCCCACCCG 37 2318 1076209 N/A N/A 97241 97256 CATTAGCACACCTTTT 122319 1076241 N/A N/A 98642 98657 CAATAAGGAACAGTTT 42 2320 1076273 N/AN/A 101849 101864 AAACAAAATGGCGAAT 84 2321 1076305 N/A N/A 104341 104356TACTAATAAGCCTCAC 37 2322 1076337 N/A N/A 107326 107341 ATTAAACCAGGGACTG25 2323 1076369 N/A N/A 110591 110606 TATTCGGTATTTTCTA 2 2324 1076401N/A N/A 112117 112132 TCTAAAGACTCTCATT 31 2325 1076433 N/A N/A 114928114943 ATTAACTTTCGCTAAA 69 2326 1076465 N/A N/A 118550 118565GCTTAAGGAATATACA 5 2327 1076497 N/A N/A 120579 120594 AAAGAATACCAACCTG72 2328 1076529 N/A N/A 40252 40267 CTATAATGAGGATTAC 108 2329 1076561N/A N/A 11318 11333 GTATACCAAGCTACTC 22 2330

TABLE 32Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 1074130214 229 3674 3689 ATCCCCCGCCCCGGCG 119 2331 1074162 338 353 3798 3813AGGCGAGCGAGGGCTA 101 2332 1074194 474 489 3934 3949 CCGGGTCCGGACGGCG 572333 1074226 859 874 7293 7308 CTGTCGAAGATGCTGA 10 2334 1074258 10441059 55539 55554 ATATTCTGCTGCACTG 36 2335 1074290 1198 1213 98900 98915CTGACTGATTCTCTGG 5 2336 1074322 1428 1443 N/A N/A AGGGCTAACTCCTGAC 942337 1074354 1613 1628 120518 120533 GGACACTGTAGCTGCT 24 2338 10743861733 1748 122758 122773 CAGGAATGGCTTCAAG 39 2339 1074418 2110 2125123135 123150 TTCTTTAGAGCCAACT 4 2340 1074450 2476 2491 123501 123516ACTAATGATAGCACTA 5 2341 1074482 2706 2721 123731 123746 TAATATGGTCATTTGC12 2342 1074514 2882 2897 123907 123922 AAGGATACATTCCACT 25 2343 10745463065 3080 124090 124105 CACTCCCCTAGGCACT 33 2344 1074578 3214 3229124239 124254 GCTTATTTCTGTCATG 8 2345 1074610 3533 3548 124558 124573TCTAGTTACATCATCT 5 2346 1074642 3830 3845 124855 124870 GGGCCAAAATACTTAG78 2347 1074674 4157 4172 125182 125197 TATAGGCACTCCTTCC 22 2348 10747064336 4351 125361 125376 TTAATGGCAGCACGGT 48 2349 1074738 4511 4526125536 125551 CTTCAGGTCAGTACAG 12 2350 1074770 4643 4658 125668 125683ATCTTATCCCAATGCT 15 2351 1074802 4836 4851 125861 125876GGCACTACATTTAGAA 37 2352 1074834 5101 5116 126126 126141TTGCGAGGATAAAATC 14 2353 1074866 5291 5306 126316 126331AACATATGAGCATGCT 30 2354 1074898 N/A N/A 5481 5496 AACTTTTGGGCAAAGT 1012355 1074930 N/A N/A 5597 5612 CTATACAACAGGCCTG 84 2356 1074962 N/A N/A5709 5724 AGGCAAGCAGCTAAAT 78 2357 1074994 N/A N/A 4784 4799AAACTAAATGGACCGG 94 2358 1075026 N/A N/A 6556 6571 CTTAAAAGCCATCTAC 552359 1075058 N/A N/A 8466 8481 ATTACAAAGTAGCAAC 66 2360 1075090 N/A N/A10590 10605 GCTTATAATCTTTCAG 9 2361 1075122 N/A N/A 12522 12537GAAAATTAGCCTACCA 16 2362 1075154 N/A N/A 16104 16119 CATTATAATGGGAGGA 132363 1075186 N/A N/A 19097 19112 AAATCGATTATTCAGA 73 2364 1075218 N/AN/A 23347 23362 CTTAACACTGGTAAGA 97 2365 1075250 N/A N/A 27030 27045AATTACGATTAGATCA 55 2366 1075282 N/A N/A 29645 29660 GAAAAATGAGCCCGGT103 2367 1075314 N/A N/A 31708 31723 AATAAAGTCTAATCCA 54 2368 1075346N/A N/A 32705 32720 GTAAGTAAAACTGCTG 16 2369 1075378 N/A N/A 35289 35304AAAACTAATCATCGAT 83 2370 1075410 N/A N/A 37572 37587 GATTAACAGCCCTTTA 362371 1075442 N/A N/A 40105 40120 TATTAGTTCTACGATT 71 2372 1075474 N/AN/A 41975 41990 TTTAATAGGCTCTATC 68 2373 1075506 N/A N/A 44427 44442CATAAAGGTGACAGCC 66 2374 1075538 N/A N/A 46165 46180 GAATTGGAACACCTCA 662375 1075570 N/A N/A 48306 48321 GATACTAAGCACAGAG 16 2376 1075602 N/AN/A 50018 50033 TATTATAAGTCTACAA 114 2377 1075634 N/A N/A 52121 52136AGACTATATTGGCTCC 65 2378 1075666 N/A N/A 53955 53970 AAATTTAGTTGTGCAC106 2379 1075698 N/A N/A 56114 56129 GTTTAATAATCCATGC 10 2380 1075730N/A N/A 58854 58869 GTATTTAAAAATAGCG 92 2381 1075762 N/A N/A 61391 61406GATAAATGGGTTGATT 20 2382 1075794 N/A N/A 63266 63281 CATAATGAATGTGGGT 382383 1075826 N/A N/A 66375 66390 TAGGGAAAACCATAGC 23 2384 1075858 N/AN/A 68977 68992 CCTTAAACAATCCCTA 23 2385 1075890 N/A N/A 72205 72220GATTAAAAGTAGGCCC 92 2386 1075922 N/A N/A 75778 75793 GCCCAAAATAGGATAC 602387 1075954 N/A N/A 78881 78896 ATTTAAGGCTGTGTTC 50 2388 1075986 N/AN/A 81253 81268 GAATATCGAAAAGCAA 26 2389 1076018 N/A N/A 83004 83019ACTAATAGGATGGATT 15 2390 1076050 N/A N/A 85864 85879 CTTTAGATTAAAGGCT 452391 1076082 N/A N/A 89791 89806 TCTCAATACACTATAT 38 2392 1076114 N/AN/A 91589 91604 ATTAGTAAGCTGAGGA 3 2393 1076146 N/A N/A 92471 92486GCTAAAACTTTCATCC 23 2394 1076178 N/A N/A 94474 94489 CCTGAAATACAGGTGT100 2395 1076210 N/A N/A 97442 97457 ATTTATATGCTCCCTC 20 2396 1076242N/A N/A 98645 98660 ATGCAATAAGGAACAG 33 2397 1076274 N/A N/A 102073102088 TGAGAATAGAGCAGGT 9 2398 1076306 N/A N/A 104347 104362CTTTACTACTAATAAG 99 2399 1076338 N/A N/A 107327 107342 CATTAAACCAGGGACT33 2400 1076370 N/A N/A 110594 110609 GATTATTCGGTATTTT 2 2401 1076402N/A N/A 112324 112339 CGTAATTATTTTTGCT 38 2402 1076434 N/A N/A 115047115062 CTTTAGGTTTATGCCT 25 2403 1076466 N/A N/A 118557 118572ATTTAGAGCTTAAGGA 5 2404 1076498 N/A N/A 120644 120659 TTACAATACCTTATGA70 2405 1076530 N/A N/A 64823 64838 AGTATAAAGCAGGGCA 5 2406 1076562 N/AN/A 12922 12937 TATTACAGAGGGTAGC 17 2407

TABLE 33Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 4 810 1074131222 237 3682 3697 GGCCCCGCATCCCCCG 72 2408 1074163 339 354 3799 3814CAGGCGAGCGAGGGCT 118 2409 1074195 475 490 3935 3950 CCCGGGTCCGGACGGC 792410 1074227 860 875 7294 7309 ACTGTCGAAGATGCTG 10 2411 1074259 10461061 55541 55556 TCATATTCTGCTGCAC 38 2412 1074291 1202 1217 98904 98919CACTCTGACTGATTCT 11 2413 1074323 1429 1444 N/A N/A CAGGGCTAACTCCTGA 1162414 1074355 1615 1630 120520 120535 AGGGACACTGTAGCTG 55 2415 10743871734 1749 122759 122774 CCAGGAATGGCTTCAA 32 2416 1074419 2111 2126123136 123151 ATTCTTTAGAGCCAAC 4 2417 1074451 2477 2492 123502 123517GACTAATGATAGCACT 6 2418 1074483 2709 2724 123734 123749 CACTAATATGGTCATT15 2419 1074515 2908 2923 123933 123948 TAACTGGAAAGCAGGG 9 2420 10745473068 3083 124093 124108 GAGCACTCCCCTAGGC 71 2421 1074579 3224 3239124249 124264 CCACTATAAAGCTTAT 6 2422 1074611 3621 3636 124646 124661TAGCTTATATTGAAGA 19 2423 1074643 3835 3850 124860 124875TTGAAGGGCCAAAATA 68 2424 1074675 4161 4176 125186 125201AAATTATAGGCACTCC 6 2425 1074707 4337 4352 125362 125377 TTTAATGGCAGCACGG36 2426 1074739 4525 4540 125550 125565 GACTCTTAGGTCTCCT 24 2427 10747714644 4659 125669 125684 AATCTTATCCCAATGC 18 2428 1074803 4837 4852125862 125877 AGGCACTACATTTAGA 32 2429 1074835 5102 5117 126127 126142CTTGCGAGGATAAAAT 30 2430 1074867 5292 5307 126317 126332TAACATATGAGCATGC 40 2431 1074899 N/A N/A 5482 5497 TAACTTTTGGGCAAAG 522432 1074931 N/A N/A 5601 5616 GAGACTATACAACAGG 35 2433 1074963 N/A N/A5710 5725 TAGGCAAGCAGCTAAA 76 2434 1074995 N/A N/A 4785 4800AAAACTAAATGGACCG 50 2435 1075027 N/A N/A 6578 6593 AAATTTGAACTGCCCA 282436 1075059 N/A N/A 8749 8764 ATTTACTTTGGATGTC 11 2437 1075091 N/A N/A10609 10624 AAACAACGAATGATTG 65 2438 1075123 N/A N/A 12563 12578CTTTAGGAAAGGGTAT 21 2439 1075155 N/A N/A 16105 16120 TCATTATAATGGGAGG 52440 1075187 N/A N/A 19108 19123 GCCCAAGGAGGAAATC 77 2441 1075219 N/AN/A 23348 23363 CCTTAACACTGGTAAG 117 2442 1075251 N/A N/A 27031 27046TAATTACGATTAGATC 79 2443 1075283 N/A N/A 29653 29668 CGAATATAGAAAAATG 902444 1075315 N/A N/A 31772 31787 CATAACTTGATGACTC 27 2445 1075347 N/AN/A 32821 32836 CATAGGTAGGCAACAA 20 2446 1075379 N/A N/A 35306 35321TACCAAAACTACAACC 75 2447 1075411 N/A N/A 37768 37783 CAAAAAGGGTAAGGCA 392448 1075443 N/A N/A 40138 40153 GATTAACAGAGCTAGA 29 2449 1075475 N/AN/A 42037 42052 TAGCAACACATGAAGA 64 2450 1075507 N/A N/A 44455 44470GTACAACCTAGTGATA 82 2451 1075539 N/A N/A 46198 46213 CTTAAGGGATGGAACA 792452 1075571 N/A N/A 48312 48327 CAAATAGATACTAAGC 54 2453 1075603 N/AN/A 50064 50079 TATGAACAAGTATGAG 35 2454 1075635 N/A N/A 52207 52222AATAAACACCTCGCCA 97 2455 1075667 N/A N/A 53956 53971 CAAATTTAGTTGTGCA109 2456 1075699 N/A N/A 56158 56173 GATTTATACTCAGGTT 4 2457 1075731 N/AN/A 58878 58893 CCCCAATATTATCTAC 40 2458 1075763 N/A N/A 61435 61450ATTTAGGCTTTGGGTT 16 2459 1075795 N/A N/A 63289 63304 GTAATTATATACCCAC 662460 1075827 N/A N/A 66457 66472 ATACTATACCTAAGGA 60 2461 1075859 N/AN/A 69260 69275 ACTTATCACTCTGCCC 20 2462 1075891 N/A N/A 72206 72221AGATTAAAAGTAGGCC 89 2463 1075923 N/A N/A 75823 75838 TTTAATACTCTCTGGG 422464 1075955 N/A N/A 79005 79020 GACCTATAATACAGAA 85 2465 1075987 N/AN/A 81256 81271 GAAGAATATCGAAAAG 13 2466 1076019 N/A N/A 83005 83020CACTAATAGGATGGAT 12 2467 1076051 N/A N/A 85945 85960 CTTAACTATTCAGCCC 212468 1076083 N/A N/A 89966 89981 CGCTATAAAGTGGCAT 46 2469 1076115 N/AN/A 91590 91605 CATTAGTAAGCTGAGG 7 2470 1076147 N/A N/A 92516 92531ATTAACTCACGAAGAC 25 2471 1076179 N/A N/A 94487 94502 AATTAGCCAACCACCT 382472 1076211 N/A N/A 97443 97458 AATTTATATGCTCCCT 22 2473 1076243 N/AN/A 98790 98805 ATATTCGATGTAACTT 41 2474 1076275 N/A N/A 102220 102235GTATTAGATAAAGCAG 10 2475 1076307 N/A N/A 104378 104393 GTAATTACCTCTAATC38 2476 1076339 N/A N/A 107352 107367 CAGCAATACTGTGGGC 13 2477 1076371N/A N/A 110712 110727 TAAGAACGAACCTCCA 49 2478 1076403 N/A N/A 112457112472 ATTTAAGACCTGGTGA 26 2479 1076435 N/A N/A 115328 115343CGTAAACATCATCTCT 12 2480 1076467 N/A N/A 118559 118574 GTATTTAGAGCTTAAG5 2481 1076499 N/A N/A 121073 121088 GCTAATATATCCAATT 37 2482 1076531N/A N/A 66739 66754 ACTATAAAGGGTTTAG 66 2483 1076563 N/A N/A 31631 31646CAAAGTAATTAAACGA 91 2484

TABLE 34Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074132223 238 3683 3698 CGGCCCCGCATCCCCC 96 2485 1074164 340 355 3800 3815CCAGGCGAGCGAGGGC 135 2486 1074196 476 491 3936 3951 GCCCGGGTCCGGACGG 992487 1074228 861 876 7295 7310 GACTGTCGAAGATGCT 17 2488 1074260 10511066 55546 55561 GTTCATCATATTCTGC 48 2489 1074292 1216 1231 98918 98933CTGTTTCACTGGAGCA 10 2490 1074324 1430 1445 N/A N/A GCAGGGCTAACTCCTG 1162491 1074356 1616 1631 120521 120536 GAGGGACACTGTAGCT 43 2492 10743881805 1820 122830 122845 GACTTGGCATCAGCTC 16 2493 1074420 2112 2127123137 123152 GATTCTTTAGAGCCAA 2 2494 1074452 2478 2493 123503 123518TGACTAATGATAGCAC 3 2495 1074484 2710 2725 123735 123750 TCACTAATATGGTCAT3 2496 1074516 2909 2924 123934 123949 TTAACTGGAAAGCAGG 22 2497 10745483093 3108 124118 124133 ATCTACCGTATGCCCA 4 2498 1074580 3225 3240 124250124265 ACCACTATAAAGCTTA 5 2499 1074612 3622 3637 124647 124662ATAGCTTATATTGAAG 12 2500 1074644 3836 3851 124861 124876ATTGAAGGGCCAAAAT 93 2501 1074676 4162 4177 125187 125202CAAATTATAGGCACTC 4 2502 1074708 4338 4353 125363 125378 CTTTAATGGCAGCACG55 2503 1074740 4526 4541 125551 125566 GGACTCTTAGGTCTCC 75 2504 10747724650 4665 125675 125690 AGTTAAAATCTTATCC 80 2505 1074804 4874 4889125899 125914 TAGCAAAGTCACTTCC 15 2506 1074836 5111 5126 126136 126151AACAACATGCTTGCGA 27 2507 1074868 5297 5312 126322 126337GTACCTAACATATGAG 74 2508 1074900 N/A N/A 5484 5499 ATTAACTTTTGGGCAA 402509 1074932 N/A N/A 5602 5617 GGAGACTATACAACAG 88 2510 1074964 N/A N/A5711 5726 TTAGGCAAGCAGCTAA 112 2511 1074996 N/A N/A 4843 4858AATAAATGCTTACGGG 60 2512 1075028 N/A N/A 6670 6685 AAAAATCAAGCCCTCG 1032513 1075060 N/A N/A 8896 8911 GTTTAACAATCTCCCC 70 2514 1075092 N/A N/A10612 10627 TTAAAACAACGAATGA 63 2515 1075124 N/A N/A 12652 12667GTAAAAACCTGGGTTT 58 2516 1075156 N/A N/A 16175 16190 ATTATATGACTCTGCT 222517 1075188 N/A N/A 19193 19208 AGTCAACCTGTAATTA 14 2518 1075220 N/AN/A 23362 23377 AATTTTAACTGTGACC 24 2519 1075252 N/A N/A 27032 27047TTAATTACGATTAGAT 90 2520 1075284 N/A N/A 29658 29673 CTTTTCGAATATAGAA 762521 1075316 N/A N/A 31797 31812 GTATATAGATACCCAC 25 2522 1075348 N/AN/A 32855 32870 TCACAAAACCCTACAC 96 2523 1075380 N/A N/A 35609 35624ACTAAAACTGACTGTC 94 2524 1075412 N/A N/A 37770 37785 TCCAAAAAGGGTAAGG 482525 1075444 N/A N/A 40268 40283 ATAAATCCTCATGTGG 112 2526 1075476 N/AN/A 42291 42306 TCTTATCCTACAGCTT 75 2527 1075508 N/A N/A 44490 44505GAAAAAGGTTTAGGGT 84 2528 1075540 N/A N/A 46199 46214 GCTTAAGGGATGGAAC 782529 1075572 N/A N/A 48372 48387 CAATTTAACTGTTACA 84 2530 1075604 N/AN/A 50104 50119 ATAATTAAGCTATCAC 81 2531 1075636 N/A N/A 52208 52223CAATAAACACCTCGCC 91 2532 1075668 N/A N/A 54032 54047 AATTATTGGTGACACT 802533 1075700 N/A N/A 56179 56194 GCCAAATAAGAGGTAG 22 2534 1075732 N/AN/A 58998 59013 AATAACCTCGAGTGCT 36 2535 1075764 N/A N/A 61668 61683CTTCAAGGAAGGTGCT 103 2536 1075796 N/A N/A 63290 63305 AGTAATTATATACCCA64 2537 1075828 N/A N/A 66513 66528 TTAGAATAGTTCTACC 59 2538 1075860 N/AN/A 69290 69305 AACTATAAGCTATGTG 73 2539 1075892 N/A N/A 72236 72251CACCAATACCAAAGTC 54 2540 1075924 N/A N/A 75824 75839 ATTTAATACTCTCTGG 212541 1075956 N/A N/A 79218 79233 TATAAAGCAATGCGAT 27 2542 1075988 N/AN/A 81357 81372 AATTAAGCTTCTCTAG 90 2543 1076020 N/A N/A 83011 83026CCCCAACACTAATAGG 60 2544 1076052 N/A N/A 86023 86038 GCAATAAAGCTGAACT 232545 1076084 N/A N/A 89980 89995 CATCAATAGAGAGTCG 7 2546 1076116 N/A N/A91600 91615 GAAAATAGCCCATTAG 25 2547 1076148 N/A N/A 92517 92532TATTAACTCACGAAGA 52 2548 1076180 N/A N/A 94489 94504 ATAATTAGCCAACCAC 422549 1076212 N/A N/A 97445 97460 CAAATTTATATGCTCC 15 2550 1076244 N/AN/A 98799 98814 CAATTTGGGATATTCG 14 2551 1076276 N/A N/A 102282 102297CTTTAGGAGTCAGAAC 59 2552 1076308 N/A N/A 104379 104394 AGTAATTACCTCTAAT32 2553 1076340 N/A N/A 107364 107379 TAATATCCTCATCAGC 8 2554 1076372N/A N/A 110715 110730 CAATAAGAACGAACCT 76 2555 1076404 N/A N/A 112458112473 TATTTAAGACCTGGTG 13 2556 1076436 N/A N/A 115413 115428CATTACTACTCTGTCC 39 2557 1076468 N/A N/A 118602 118617 CATTACTACTAAGAGT91 2558 1076500 N/A N/A 121129 121144 CAATTAAGATCAACAT 99 2559 1076532N/A N/A 68936 68951 ATTTTTAGGCAGACGC 12 2560 1076564 N/A N/A 39617 39632TAAAGTAATGCTACAG 77 2561

TABLE 35Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 1074133224 239 3684 3699 GCGGCCCCGCATCCCC 101 2562 1074165 341 356 3801 3816CCCAGGCGAGCGAGGG 90 2563 1074197 477 492 3937 3952 TGCCCGGGTCCGGACG 912564 1074229 864 879 7298 7313 GAAGACTGTCGAAGAT 5 2565 1074261 1055 107055550 55565 CCGAGTTCATCATATT 19 2566 1074293 1217 1232 98919 98934GCTGTTTCACTGGAGC 54 2567 1074325 1431 1446 116620 116635CGCAGGGCTAACTCCT 42 2568 1074357 1617 1632 120522 120537CGAGGGACACTGTAGC 12 2569 1074389 1808 1823 122833 122848GCAGACTTGGCATCAG 14 2570 1074421 2113 2128 123138 123153TGATTCTTTAGAGCCA 3 2571 1074453 2479 2494 123504 123519 GTGACTAATGATAGCA4 2572 1074485 2711 2726 123736 123751 TTCACTAATATGGTCA 4 2573 10745172939 2954 123964 123979 AATGCATACAAAGCGC 55 2574 1074549 3094 3109124119 124134 TATCTACCGTATGCCC 6 2575 1074581 3226 3241 124251 124266AACCACTATAAAGCTT 18 2576 1074613 3623 3638 124648 124663CATAGCTTATATTGAA 7 2577 1074645 3837 3852 124862 124877 AATTGAAGGGCCAAAA81 2578 1074677 4169 4184 125194 125209 CTACTGGCAAATTATA 22 2579 10747094352 4367 125377 125392 TCTAGAACAGCTGCCT 71 2580 1074741 4528 4543125553 125568 AAGGACTCTTAGGTCT 78 2581 1074773 4651 4666 125676 125691CAGTTAAAATCTTATC 94 2582 1074805 4875 4890 125900 125915GTAGCAAAGTCACTTC 9 2583 1074837 5112 5127 126137 126152 TAACAACATGCTTGCG11 2584 1074869 5298 5313 126323 126338 AGTACCTAACATATGA 31 2585 1074901N/A N/A 5485 5500 TATTAACTTTTGGGCA 61 2586 1074933 N/A N/A 5603 5618AGGAGACTATACAACA 72 2587 1074965 N/A N/A 5715 5730 GTGTTTAGGCAAGCAG 202588 1074997 N/A N/A 4854 4869 GCCGCGAGGAAAATAA 119 2589 1075029 N/A N/A7004 7019 ATATTCGACACTGGAG 33 2590 1075061 N/A N/A 8954 8969CCTTATACTTTTAGCC 5 2591 1075093 N/A N/A 10664 10679 CAAAGTAAGGTATGAG 32592 1075125 N/A N/A 12777 12792 CTTAAGGTACAAGGCA 84 2593 1075157 N/AN/A 16192 16207 CCAGAAAATCATAGTA 19 2594 1075189 N/A N/A 19238 19253GCTAATAGTCACTGTT 11 2595 1075221 N/A N/A 23384 23399 CATTATCCGGGAGAGC 102596 1075253 N/A N/A 27033 27048 GTTAATTACGATTAGA 20 2597 1075285 N/AN/A 29702 29717 TATACATAGTCAATTC 60 2598 1075317 N/A N/A 31832 31847GTATTCGCCTCCTGCA 27 2599 1075349 N/A N/A 33000 33015 ATTAAAGCTCATTGAT 812600 1075381 N/A N/A 35767 35782 TATTACCCTACTCATA 89 2601 1075413 N/AN/A 37807 37822 CATAACTACATCGACA 34 2602 1075445 N/A N/A 40269 40284TATAAATCCTCATGTG 84 2603 1075477 N/A N/A 42405 42420 CTTTATCTCACTAGCT 862604 1075509 N/A N/A 44622 44637 CATAATCCCTGACTTG 81 2605 1075541 N/AN/A 46250 46265 GCTCAAAACTGACATA 47 2606 1075573 N/A N/A 48504 48519AAGGAACCTTCTGTGT 72 2607 1075605 N/A N/A 50176 50191 CGTAAACATTTTGCCT 382608 1075637 N/A N/A 52219 52234 CCACAACCTGTCAATA 100 2609 1075669 N/AN/A 54033 54048 AAATTATTGGTGACAC 70 2610 1075701 N/A N/A 56296 56311AATTACTAGAGGCTTC 3 2611 1075733 N/A N/A 58999 59014 CAATAACCTCGAGTGC 282612 1075765 N/A N/A 61721 61736 CTTAAGGCAGCTCTAT 58 2613 1075797 N/AN/A 63378 63393 GATAATCATGATACTC 3 2614 1075829 N/A N/A 66603 66618ACTCAATAGATCATTG 41 2615 1075861 N/A N/A 69291 69306 TAACTATAAGCTATGT 782616 1075893 N/A N/A 72284 72299 CGTGAAAAAGATGTGG 7 2617 1075925 N/A N/A75907 75922 AACCTATATTATTTGC 28 2618 1075957 N/A N/A 79219 79234CTATAAAGCAATGCGA 28 2619 1075989 N/A N/A 81362 81377 GCTAAAATTAAGCTTC 782620 1076021 N/A N/A 83058 83073 CATTAATAAAGTTACC 95 2621 1076053 N/AN/A 86047 86062 TACCAACAAGGCATCA 55 2622 1076085 N/A N/A 90079 90094ACTAATAGGCCATCTG 7 2623 1076117 N/A N/A 91603 91618 CTAGAAAATAGCCCAT 152624 1076149 N/A N/A 92518 92533 TTATTAACTCACGAAG 24 2625 1076181 N/AN/A 94490 94505 TATAATTAGCCAACCA 26 2626 1076213 N/A N/A 97518 97533TCTCAAGGAATTGCCT 27 2627 1076245 N/A N/A 98849 98864 CCTAAAAAACTAGTGA101 2628 1076277 N/A N/A 102574 102589 GCTAAAACATCAGATA 24 2629 1076309N/A N/A 104525 104540 GATAACTTTCCACAAT 9 2630 1076341 N/A N/A 107422107437 ATTAACTACAACTGTG 18 2631 1076373 N/A N/A 111082 111097AACGGATATACAATAA 10 2632 1076405 N/A N/A 112459 112474 TTATTTAAGACCTGGT12 2633 1076437 N/A N/A 115843 115858 GAAGAATAGCATCTGA 19 2634 1076469N/A N/A 118627 118642 GTAAAAGGGAACTAAG 69 2635 1076501 N/A N/A 121268121283 CATAACACTTAAGGTG 97 2636 1076533 N/A N/A 75580 75595ATTTTTAGTCCAGTGG 9 2637 1076565 N/A N/A 55334 55349 CATTAAGTCACAGCAT 742638

TABLE 36Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 1 810 1074134225 240 3685 3700 CGCGGCCCCGCATCCC 79 2639 1074166 342 357 3802 3817ACCCAGGCGAGCGAGG 72 2640 1074198 478 493 3938 3953 TTGCCCGGGTCCGGAC 1122641 1074230 866 881 7300 7315 AAGAAGACTGTCGAAG 4 2642 1074262 1056 107155551 55566 GCCGAGTTCATCATAT 48 2643 1074294 1275 1290 98977 98992TTGGAGTTGCTGCCAC 80 2644 1074326 1432 1447 116621 116636ACGCAGGGCTAACTCC 36 2645 1074358 1618 1633 120523 120538TCGAGGGACACTGTAG 17 2646 1074390 1810 1825 122835 122850CTGCAGACTTGGCATC 64 2647 1074422 2189 2204 123214 123229AAACAGGCTCACTTCC 9* 2648 1074454 2480 2495 123505 123520TGTGACTAATGATAGC 1 2649 1074486 2712 2727 123737 123752 ATTCACTAATATGGTC4 2650 1074518 2940 2955 123965 123980 AAATGCATACAAAGCG 13 2651 10745503095 3110 124120 124135 ATATCTACCGTATGCC 23 2652 1074582 3228 3243124253 124268 TAAACCACTATAAAGC 18 2653 1074614 3624 3639 124649 124664TCATAGCTTATATTGA 49 2654 1074646 3838 3853 124863 124878AAATTGAAGGGCCAAA 39 2655 1074678 4179 4194 125204 125219TAATCTGTGGCTACTG 7 2656 1074710 4353 4368 125378 125393 CTCTAGAACAGCTGCC42 2657 1074742 4529 4544 125554 125569 AAAGGACTCTTAGGTC 25 2658 10747744661 4676 125686 125701 CAAGAATACCCAGTTA 16 2659 1074806 4877 4892125902 125917 TTGTAGCAAAGTCACT 8 2660 1074838 5113 5128 126138 126153ATAACAACATGCTTGC 9 2661 1074870 5301 5316 126326 126341 GTAAGTACCTAACATA20 2662 1074902 N/A N/A 5486 5501 CTATTAACTTTTGGGC 54 2663 1074934 N/AN/A 5604 5619 CAGGAGACTATACAAC 74 2664 1074966 N/A N/A 5721 5736ATTGAAGTGTTTAGGC 9 2665 1074998 N/A N/A 4998 5013 CACGCGACCTACTAAG 612666 1075030 N/A N/A 7007 7022 TTAATATTCGACACTG 37 2667 1075062 N/A N/A8960 8975 CTTTAACCTTATACTT 58 2668 1075094 N/A N/A 10705 10720GATAAATGTAACTAGC 10 2669 1075126 N/A N/A 12890 12905 CTTAAATCTTAGCAAC 202670 1075158 N/A N/A 16240 16255 CGGCAAAAACAAAATC 76 2671 1075190 N/AN/A 19295 19310 TATCAAGGATTCAGTA 45 2672 1075222 N/A N/A 23766 23781GTATTTGGACAACTCT 3 2673 1075254 N/A N/A 27099 27114 TCCCAAAAGTCATCGC 282674 1075286 N/A N/A 29807 29822 ATTACGGACAGAAGTG 48 2675 1075318 N/AN/A 31850 31865 ATCCTAAAGCCACTGC 72 2676 1075350 N/A N/A 33001 33016GATTAAAGCTCATTGA 62 2677 1075382 N/A N/A 35769 35784 ATTATTACCCTACTCA 332678 1075414 N/A N/A 37990 38005 CATACTAATCCCTCTT 41 2679 1075446 N/AN/A 40270 40285 CTATAAATCCTCATGT 87 2680 1075478 N/A N/A 42416 42431CATTTTGAACCCTTTA 20 2681 1075510 N/A N/A 44630 44645 GAATAACACATAATCC 832682 1075542 N/A N/A 46607 46622 TGAGAAAGGTTCCTGA 66 2683 1075574 N/AN/A 48508 48523 AGTCAAGGAACCTTCT 47 2684 1075606 N/A N/A 50368 50383GCTAAACCTACACGCT 82 2685 1075638 N/A N/A 52324 52339 ATTAACCAGAAGCCTG 792686 1075670 N/A N/A 54501 54516 TATATATGATGGACTG 39 2687 1075702 N/AN/A 56442 56457 GAGGAAGGGCACCTTT 81 2688 1075734 N/A N/A 59002 59017AGGCAATAACCTCGAG 26 2689 1075766 N/A N/A 61741 61756 GGAGAACACAAGAGGC 52690 1075798 N/A N/A 63396 63411 ATTTAGATAGTTACTG 21 2691 1075830 N/AN/A 66610 66625 GATGAACACTCAATAG 12 2692 1075862 N/A N/A 70001 70016CTAATAACTTGTCTAC 67 2693 1075894 N/A N/A 72305 72320 CTCGAAAGCTGGGCCC100 2694 1075926 N/A N/A 75911 75926 GTAGAACCTATATTAT 25 2695 1075958N/A N/A 79351 79366 CATTATGACATTCCCC 12 2696 1075990 N/A N/A 81490 81505CGTTATTATGCAGCAA 1 2697 1076022 N/A N/A 83093 83108 TAATTAGATGCTGACA 22698 1076054 N/A N/A 86104 86119 CATTAGACTTTCTGTC 21 2699 1076086 N/AN/A 90080 90095 AACTAATAGGCCATCT 31 2700 1076118 N/A N/A 91688 91703CGTAAATTGAGGCCCA 45 2701 1076150 N/A N/A 92520 92535 ATTTATTAACTCACGA 112702 1076182 N/A N/A 94491 94506 CTATAATTAGCCAACC 15 2703 1076214 N/AN/A 97543 97558 ATCCTATACATTAAGA 67 2704 1076246 N/A N/A 98850 98865TCCTAAAAAACTAGTG 75 2705 1076278 N/A N/A 102644 102659 AATAAGGACAGGACCC29 2706 1076310 N/A N/A 104554 104569 ACCCTATACTTGAATT 36 2707 1076342N/A N/A 107423 107438 CATTAACTACAACTGT 33 2708 1076374 N/A N/A 111084111099 ATAACGGATATACAAT 15 2709 1076406 N/A N/A 112460 112475ATTATTTAAGACCTGG 4 2710 1076438 N/A N/A 115846 115861 TAGGAAGAATAGCATC13 2711 1076470 N/A N/A 118843 118858 GATAAAGAGGTTAACA 34 2712 1076502N/A N/A 121320 121335 CAAAGTAAGTGAGCCC 17 2713 1076534 N/A N/A 7922079235 ACTATAAAGCAATGCG 4 2714 1076566 N/A N/A 55576 55591AATTACAGTGTCTCAC 63 2715

TABLE 37Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 YAP1 Compund StartStop Start Stop (% SEQ Number Site Site Site Site Sequence (5' to 3')UTC) ID NO 958499 2565 2580 123590 123605 ATTAGAGTATGTGGCA 2 810 1074135226 241 3686 3701 CCGCGGCCCCGCATCC 91 2716 1074167 353 368 3813 3828CGCACCCCCTGACCCA 58 2717 1074199 483 498 3943 3958 GCCGGTTGCCCGGGTC 1012718 1074231 867 882 7301 7316 AAAGAAGACTGTCGAA 8 2719 1074263 1057 107255552 55567 AGCCGAGTTCATCATA 34 2720 1074295 1278 1293 98980 98995TGGTTGGAGTTGCTGC 15 2721 1074327 1433 1448 116622 116637TACGCAGGGCTAACTC 39 2722 1074359 1619 1634 120524 120539TTCGAGGGACACTGTA 18 2723 1074391 1828 1843 122853 122868GTCAGAACTCAAAGCT 14 2724 1074423 2190 2205 123215 123230CAAACAGGCTCACTTC 4* 2725 1074455 2485 2500 123510 123525CATTATGTGACTAATG 67 2726 1074487 2714 2729 123739 123754AGATTCACTAATATGG 7 2727 1074519 2959 2974 123984 123999 ACTACTAGTCATGTAT45 2728 1074551 3096 3111 124121 124136 AATATCTACCGTATGC 58 2729 10745833229 3244 124254 124269 GTAAACCACTATAAAG 30 2730 1074615 3625 3640124650 124665 TTCATAGCTTATATTG 8 2731 1074647 3839 3854 124864 124879CAAATTGAAGGGCCAA 27 2732 1074679 4182 4197 125207 125222TCTTAATCTGTGGCTA 5 2733 1074711 4354 4369 125379 125394 ACTCTAGAACAGCTGC28 2734 1074743 4530 4545 125555 125570 GAAAGGACTCTTAGGT 16 2735 10747754681 4696 125706 125721 GGTTTATTGTAAAAGC 3 2736 1074807 4927 4942 125952125967 CCATATAGAAGGCATG 75 2737 1074839 5114 5129 126139 126154TATAACAACATGCTTG 33 2738 1074871 5302 5317 126327 126342TGTAAGTACCTAACAT 70 2739 1074903 N/A N/A 5487 5502 CCTATTAACTTTTGGG 872740 1074935 N/A N/A 5605 5620 ACAGGAGACTATACAA 80 2741 1074967 N/A N/A5726 5741 GACAAATTGAAGTGTT 116 2742 1074999 N/A N/A 5004 5019AACCAACACGCGACCT 77 2743 1075031 N/A N/A 7009 7024 ATTTAATATTCGACAC 522744 1075063 N/A N/A 9104 9119 TACGGAAGGCCAACTG 16 2745 1075095 N/A N/A10722 10737 CTTGAAAACAAGCCAC 63 2746 1075127 N/A N/A 12934 12949GCTAAATTATGCTATT 79 2747 1075159 N/A N/A 16250 16265 CAAAAAATCACGGCAA 632748 1075191 N/A N/A 19412 19427 ACGGGAAAGAAAGGCC 83 2749 1075223 N/AN/A 23854 23869 GTTAAAAGTGAACCCA 19 2750 1075255 N/A N/A 27113 27128AAATATCCGTGTCCTC 16 2751 1075287 N/A N/A 29808 29823 TATTACGGACAGAAGT 582752 1075319 N/A N/A 31860 31875 TATAACAATCATCCTA 59 2753 1075351 N/AN/A 33002 33017 AGATTAAAGCTCATTG 38 2754 1075383 N/A N/A 35770 35785AATTATTACCCTACTC 45 2755 1075415 N/A N/A 38069 38084 CATTAAATGACAGCCT 522756 1075447 N/A N/A 40272 40287 CACTATAAATCCTCAT 96 2757 1075479 N/AN/A 42463 42478 GACAATAAATCTGCCT 77 2758 1075511 N/A N/A 44708 44723CAATATTATCTGAGCT 106 2759 1075543 N/A N/A 46674 46689 ATATATTAGGAGTTTC22 2760 1075575 N/A N/A 48710 48725 TTACAACACAAGTCTA 55 2761 1075607 N/AN/A 50539 50554 AAAACGGTGTGAAGAA 45 2762 1075639 N/A N/A 52325 52340AATTAACCAGAAGCCT 101 2763 1075671 N/A N/A 54503 54518 GATATATATGATGGAC37 2764 1075703 N/A N/A 56609 56624 GGAGAAAGCCATCAAG 10 2765 1075735 N/AN/A 59100 59115 GAATCGATGTGTTGCG 17 2766 1075767 N/A N/A 61758 61773TATTACACAGGCAGGC 12 2767 1075799 N/A N/A 63412 63427 CCTCAACACATTTGAG 852768 1075831 N/A N/A 66680 66695 TATTAGCCTTCTAACC 59 2769 1075863 N/AN/A 70002 70017 CCTAATAACTTGTCTA 71 2770 1075895 N/A N/A 72306 72321ACTCGAAAGCTGGGCC 38 2771 1075927 N/A N/A 75923 75938 GCTTAAAATCATGTAG 322772 1075959 N/A N/A 79446 79461 GATTATTATTGCAGCT 15 2773 1075991 N/AN/A 81533 81548 ATATAGGACCACGACT 62 2774 1076023 N/A N/A 83094 83109ATAATTAGATGCTGAC 4 2775 1076055 N/A N/A 86186 86201 AATTACTAACAATCTC 452776 1076087 N/A N/A 90082 90097 CAAACTAATAGGCCAT 10 2777 1076119 N/AN/A 91742 91757 GTTAAATATGAATTGG 7 2778 1076151 N/A N/A 92521 92536TATTTATTAACTCACG 14 2779 1076183 N/A N/A 94494 94509 CTTCTATAATTAGCCA 72780 1076215 N/A N/A 97620 97635 TTATAACAGACTGGCT 47 2781 1076247 N/AN/A 99297 99312 GACCAAAACAGCTCTT 11 2782 1076279 N/A N/A 102645 102660CAATAAGGACAGGACC 71 2783 1076311 N/A N/A 104558 104573 TATAACCCTATACTTG56 2784 1076343 N/A N/A 107707 107722 AGACTAAATCTTCCCT 8 2785 1076375N/A N/A 111085 111100 TATAACGGATATACAA 22 2786 1076407 N/A N/A 112462112477 GTATTATTTAAGACCT 22 2787 1076439 N/A N/A 115906 115921CTTATATGGTTTTGTG 4 2788 1076471 N/A N/A 118862 118877 CATTAGACTAGGCTTT 52789 1076503 N/A N/A 121702 121717 AATTACCCCTGTGAGG 77 2790 1076535 N/AN/A 83322 83337 ATTTTTAGCTCGCAAT 28 2791 1076567 N/A N/A 59365 59380GATTACAGTGACATTC 10 2792

TABLE 32 Inhibition of Yap1 mRNA by 3-10-3 cEt gapmerstargeting SEQ ID NO.: 3 SEQ ID SEQ ID NO: 3 NO: 3 YAP1 Compund StartStop % SEQ Number Site Site Sequence (5' to 3') UTC) ID NO 1074880 12461261 CTCCTGCCGAAGCAGT 101 2793 1074881 1250 1265 CTAACTCCTGCCGAAG 762794 1074882 1251 1266 GCTAACTCCTGCCGAA 73 2795 1074883 1252 1267GGCTAACTCCTGCCGA 107 2796 1074884 1253 1268 GGGCTAACTCCTGCCG 110 27971074885 1254 1269 AGGGCTAACTCCTGCC 115 2798 1074886 1255 1270CAGGGCTAACTCCTGC 104 2799

Example 5 Antisense Inhibition of Human Yap1 in SNU-449 Cells byModified Oligonucleotides

Modified oligonucleotides with additional chemistry modifications weredesigned to target a Yap1 nucleic acid and were tested for their effecton Yap1 mRNA level in SNU-449 cells. The modified oligonucleotides weretested in a series of experiments that had similar culture conditions.The results for each experiment are presented in separate tables shownbelow. Cultured SNU-449 cells at a density of 10,000 cells per well weretreated using free uptake with 2,000 nM of modified oligonucleotide.After a treatment period of approximately 48 hours, RNA was isolatedfrom the cells and Yap1 mRNA levels were measured by quantitativereal-time RTPCR. Human primer probe set RTS36584 was used to measuremRNA levels. Yap1 mRNA levels were normalized to total RNA content, asmeasured by RIBOGREEN®. Results are presented in the tables below aspercent control of the amount of Yap1 mRNA relative to untreated controlcells (% UTC). The modified oligonucleotides with percent control valuesmarked with an asterisk (*) target the amplicon region of the primerprobe set. Additional assays may be used to measure the potency andefficacy of the modified oligonucleotides targeting the amplicon region.

Several different chemistry modifications were tested, which arespecified in the Chemistry Notation column of the tables below, whereinthe notation “d” refers to a 2′-deoxyribose sugar, the notation “s”refers to a phosphorothioate (P═S) internucleoside linkage, the notation“k” refers to a cEt modified sugar, the notation “y” refers to a2′-O-methyl ribose sugar, the notation “e” refers to a MOE modifiedsugar, and the notation “^(m)C” refers to a 5-methylcytosine.

“Start site” indicates the 5′-most nucleoside to which the gapmer istargeted in the human gene sequence. “Stop site” indicates the 3′-mostnucleoside to which the gapmer is targeted human gene sequence. Eachgapmer listed in the Tables below is targeted to either SEQ ID NO.: 1 orSEQ ID NO.: 2. ‘N/A’ indicates that the modified oligonucleotide doesnot target that particular gene sequence with 100% complementarity.‘N.D.’ indicates that the % UTC is not defined for that particularmodified oligonucleotide in that particular experiment. Activity of themodified oligonucleotide may be defined in a different experiment.

TABLE 39Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ ID ID SEQ SEQ NO: 1 NO: 1 ID NO: ID NO: YAP1 SEQ Compound StartStop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5' to 3')CHEMISTRY NOTATION UTC) NO 715487 3630 3645 124655 124670ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 12 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 8 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds) 7 2800 T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1095379 4443 4458 125468 125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds) 52 392T_(ds)A_(ds)A_(ks) ^(m)C_(es)T_(ks)G_(es)G_(k) 1095397 4441 4456 125466125481 TGAGGTATAACTGGGCT_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 531580 C_(ds)T_(ks)G_(es)G_(ks)G_(es) ^(m)C_(k) 1095398 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 38 2801A_(ds)A_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(es)G_(k) 1095399 4444 4459 125469125484 CACTGAGGTATAACTG ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 46 2802A_(ds)T_(ds)A_(ks)A_(es) ^(m)C_(ks)T_(es)G_(k) 1198370 2524 2539 123549123564 TGTCTCATGCCTTATA T_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m) 20 2803 C_(ds)^(m)C_(ds)T_(ks)T_(es)A_(ks)T_(es)A_(k) 1198371 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds) 15 2804 T_(ds)G_(ds) ^(m)C_(ks)^(m)C_(es)T_(ks)T_(es)A_(k) 1198372 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 21 2805 A_(ds)T_(ds)G_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es)T_(k)1198373 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 40 443C_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks) ^(m)C_(es)T_(k) 1198374 2529 2544123554 123569 GAAATTGTCTCATGCCG_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 24 2800T_(ds) ^(m)C_(ds)A_(ks)T_(es)G_(ks) ^(m)C_(es) ^(m)C_(k) 1198375 25302545 123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 22 2806C_(ds)T_(ds) ^(m)C_(ks)A_(es)T_(ks)G_(es) ^(m)C_(k) 1198376 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 362807 C_(ds)T_(ks) ^(m)C_(es)A_(ks)T_(es)G_(k) 1198377 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 30 2808T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(es)T_(k) 1198378 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 39 656T_(ds)G_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 1198379 2560 2575 123585123600 AGTATGTGGCAATAATA_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m) 45 2809C_(ds)A_(ds)A_(ks)T_(es)A_(ks)A_(es)T_(k) 1198380 2562 2577 123587123602 AGAGTATGTGGCAATAA_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 18 2810G_(ds) ^(m)C_(ks)A_(es)A_(ks)T_(es)A_(k) 1198381 2563 2578 123588 123603TAGAGTATGTGGCAATT_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 19 2811G_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(es)T_(k) 1198382 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 19 963T_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(es)A_(k) 1198383 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 31 810G_(ds)T_(ks)G_(es)G_(ks) ^(m)C_(es)A_(k) 1198384 2566 2581 123591 123606TATTAGAGTATGTGGCT_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 6 2812T_(ds)G_(ks)T_(es)G_(ks)G_(es) ^(m)C_(k) 1198385 2567 2582 123592 123607ATATTAGAGTATGTGGA_(ks)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 30 2813A_(ds)T_(ks)G_(es)T_(ks)G_(es)G_(k) 1198386 2568 2583 123593 123608TATATTAGAGTATGTGT_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 77 2814T_(ds)A_(ks)T_(es)G_(ks)T_(es)G_(k) 1198387 2570 2585 123595 123610TCTATATTAGAGTATG T_(ks)^(m)C_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 84 887A_(ds)G_(ks)T_(es)A_(ks)T_(es)G_(k) 1198388 4436 4451 125461 125476TATAACTGGGCAAATT T_(ks)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds) 90 2815 G_(ds)^(m)C_(ds)A_(ks)A_(es)A_(ks)T_(es)T_(k) 1198389 4438 4453 125463 125478GGTATAACTGGGCAAA G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds) 28 1427 G_(ds)G_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(es)A_(k)1198390 4439 4454 125464 125479 AGGTATAACTGGGCAAA_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) 37 905T_(ds)G_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(es)A_(k) 1198391 4440 4455 125465125480 GAGGTATAACTGGGCAG_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 29 1503C_(ds)T_(ds)G_(ks)G_(es)G_(ks) ^(m)C_(es)A_(k) 1198392 4446 4461 125471125486 AACACTGAGGTATAAC A_(ks)A_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 48 2816G_(ds)T_(ds)A_(ks)T_(es)A_(ks)A_(es) ^(m)C_(k) 1198393 4595 4610 125620125635 TTACATTAGGAACAAG T_(ks)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 58 2817 G_(ds)A_(ds)A_(ks)^(m)C_(es)A_(ks)A_(es)G_(k) 1198394 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 63 2818 G_(ds)G_(ks)A_(es)A_(ks)^(m)C_(es)A_(k) 1198395 4598 4613 125623 125638 CTTTTACATTAGGAAC^(m)C_(ks)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) 35 1124T_(ds)A_(ds)G_(ks)G_(es)A_(ks)A_(es) ^(m)C_(k) 1198396 4599 4614 125624125639 ACTTTTACATTAGGAA A_(ks) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 25 2819 T_(ds)T_(ds)A_(ks)G_(es)G_(ks)A_(es)A_(k)1198397 4600 4615 125625 125640 CACTTTTACATTAGGA ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 17 1200A_(ds)T_(ds)T_(ks)A_(es)G_(ks)G_(es)A_(k) 1198398 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks)^(m)C_(ds)A_(ds)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 18 1276C_(ds)A_(ds)T_(ks)T_(es)A_(ks)G_(es)G_(k) 1198399 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 35 2820 A_(ds)^(m)C_(ds)A_(ks)T_(es)T_(ks)A_(es)G_(k) 1198400 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 62 2821 T_(ds)A_(ds)^(m)C_(ks)A_(es)T_(ks)T_(es)A_(k) 1198401 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ds)A_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 63 2822 T_(ds)T_(ds)T_(ks)A_(es) ^(m)C_(ks)A_(es)T_(k)1198402 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 32 2823G_(ds)A_(ds)A_(ks)A_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 1198403 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 54 2824C_(ds)T_(ds)G_(ks)A_(es)A_(ks)A_(es) ^(m)C_(k) 1198404 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 552825 C_(ds)T_(ks)G_(es)A_(ks)A_(es)A_(k) 1198405 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 36 2826A_(ds)T_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(es)A_(k) 1198406 4800 4815 125825125840 GCTTTGGAAGATCTGA G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 17 2044G_(ds)A_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(es)A_(k) 1198407 4801 4816 125826125841 TGCTTTGGAAGATCTG T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) 23 2121A_(ds)G_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(es)G_(k) 1198408 4802 4817 125827125842 GTGCTTTGGAAGATCT G_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 41 2827A_(ds)A_(ds)G_(ks)A_(es)T_(ks) ^(m)C_(es)T_(k) 1198409 4803 4818 125828125843 AGTGCTTTGGAAGATC A_(ks)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds) 19 2828G_(ds)A_(ds)A_(ks)G_(es)A_(ks)T_(es) ^(m)C_(k) 1198410 4805 4820 125830125845 ATAGTGCTTTGGAAGA A_(ks)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 48 2829 G_(ds)G_(ks)A_(es)A_(ks)G_(es)A_(k)1198411 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) 33 2830G_(ds)G_(ds)T_(ks)T_(es)T_(ks)T_(es)T_(k) 1198412 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds) 17 2831 A_(ds)T_(ds)G_(ks)G_(es)T_(ks)T_(es)T_(k) 1198413 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 29 2832C_(ds)A_(ds)T_(ks)G_(es)G_(ks)T_(es)T_(k) 1198414 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 202833 C_(ds)A_(ks)T_(es)G_(ks)G_(es)T_(k) 1198415 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 29 2834G_(ds) ^(m)C_(ks)A_(es)T_(ks)G_(es)G_(k) 1198416 N/A N/A 94735 94750AGATTTAGGATGCATGA_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 29 2835T_(ds)G_(ks) ^(m)C_(es)A_(ks)T_(es)G_(k) 1198417 N/A N/A 94736 94751CAGATTTAGGATGCAT^(m)C_(ks)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 40 2836G_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks)A_(es)T_(k) 1198418 N/A N/A 9473794752 TCAGATTTAGGATGCA T_(ks)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds) 67 2837G_(ds)G_(ds)A_(ks)T_(es)G_(ks) ^(m)C_(es)A_(k) 1198419 N/A N/A 9473994754 ATTCAGATTTAGGATG A_(ks)T_(ds)T_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds) 78 2838A_(ds)G_(ks)G_(es)A_(ks)T_(es)G_(k) 1198420 N/A N/A 115903 115918ATATGGTTTTGTGTGTA_(ks)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 41 2839G_(ds)T_(ks)G_(es)T_(ks)G_(es)T_(k) 1198421 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 36 2840T_(ds)T_(ks)G_(es)T_(ks)G_(es)T_(k) 1198422 N/A N/A 115906 115921CTTATATGGTTTTGTG^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(s)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 18 2788T_(ds)T_(ks)T_(es)G_(ks)T_(es)G_(k) 1198423 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks)^(m)C_(ds)T_(ds+lTs)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 10 2841T_(ds)T_(ks)T_(es)T_(ks)G_(es)T_(k) 1198424 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 15 2842G_(ds)G_(ds)T_(ks)T_(es)T_(ks)T_(es)G_(k) 1198429 N/A N/A 117325 117340ATTGCAATCTGTCTGA A_(ks)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 48 2843 T_(ds)G_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(es)A_(k)1198430 N/A N/A 117327 117342 ATATTGCAATCTGTCTA_(ks)T_(ds)A_(ds)T_(ds)T_(ds)C_(ds) ^(m)C_(ds)A_(ds)A_(ds) 49 2844T_(ds) ^(m)C_(ds)T_(ks)G_(es)T_(ks) ^(m)C_(es)T_(k) 1198431 N/A N/A117328 117343 AATATTGCAATCTGTCA_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 35 2845A_(ds)T_(ds) ^(m)C_(ks)T_(es)G_(ks)T_(es) ^(m)C_(k) 1198432 N/A N/A117329 117344 TAATATTGCAATCTGTT_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 70 2846A_(ds)A_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(es)T_(k) 1198433 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 36 1404C_(ds)A_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(es)G_(k) 1198434 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 782847 C_(ds)A_(ks)A_(es)T_(ks) ^(m)C_(es)T_(k) 1198435 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 57 2848G_(ds) ^(m)C_(ks)A_(es)A_(ks)T_(es) ^(m)C_(k) 1198436 N/A N/A 117333117348 TATGTAATATTGCAATT_(ks)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 69 2849T_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(es)T_(k) 1198437 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 63 2850A_(ds)T_(ks)T_(es)G_(ks) ^(m)C_(es)A_(k) 1198447 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(s)^(m)C_(ds) ^(m) 63 2851 C_(ds) ^(m)C_(ds)A_(ks)G_(es)A_(ks)T_(es)T_(k)1198448 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 362852 C_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)A_(k) 1198449 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 37 2853T_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(k) 1198450 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 42 2854T_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 1198451 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 48 1101G_(ds)T_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(k) 1198452 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 38 2855G_(ds)G_(ds)T_(ks)T_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 1198453 N/A N/A119674 119689 GACTAAGTAAGGTTTC G_(ks)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 48 2856A_(ds)G_(ds)G_(ks)T_(es)T_(ks)T_(es) ^(m)C_(k) 1198454 N/A N/A 119675119690 AGACTAAGTAAGGTTT A_(ks)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 39 2857A_(ds)A_(ds)G_(ks)G_(es)T_(ks)T_(es)T_(k) 1198455 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds) 42 2858G_(ds)T_(ds)A_(ks)A_(es)G_(ks)G_(es)T_(k)

TABLE 40Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ ID ID SEQ SEQ NO: 1 NO: 1 ID NO: ID NO: YAP1 SEQ Compound StartStop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5' to 3')CHEMISTRY NOTATION UTC) NO 715487 3630 3645 124655 124670ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 28 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 15 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 9 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1198425 N/A N/A 115909 115924 ACTCTTATATGGTTTT A_(ks)^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 35 2859T_(ds)G_(ds)G_(ks)T_(es)T_(ks)T_(es)T_(k) 1198426 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 111 2860A_(ds)T_(ds)G_(ks)G_(es)T_(ks)T_(es)T_(k) 1198427 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 62 2861T_(ds)A_(ds)T_(ks)G_(es)G_(ks)T_(es)T_(k) 1198428 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(ds) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds) 62 2862 T_(ds)A_(ds)T_(ks)A_(es)T_(ks)G_(es)G_(k)1198438 N/A N/A 117755 117770 TGTATGTCAGAAGAGTT_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds) 7 2863A_(ds)A_(ks)G_(es)A_(ks)G_(es)T_(k) 1198439 N/A N/A 117757 117772AGTGTATGTCAGAAGA A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds) 6 2864 A_(ds)G_(ks)A_(es)A_(ks)G_(es)A_(k) 1198440 N/A N/A117758 117773 AAGTGTATGTCAGAAGA_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 5 2865C_(ds)A_(ks)G_(es)A_(ks)A_(es)G_(k) 1198441 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 19 2866T_(ds) ^(m)C_(ks)A_(es)G_(ks)A_(es)A_(k) 1198442 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 44 2867G_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(es)A_(k) 1198443 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 39 2868T_(ds)G_(ks)T_(es) ^(m)C_(ks)A_(es)G_(k) 1198444 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 70 2869A_(ds)T_(ks)G_(es)T_(ks) ^(m)C_(es)A_(k) 1198445 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 61 1634T_(ds)A_(ks)T_(es)G_(ks)T_(es) ^(m)C_(k) 1198446 N/A N/A 117765 117780AACTTTAAAGTGTATG A_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) 83 2870T_(ds)G_(ks)T_(es)A_(ks)T_(es)G_(k) 1198714 2524 2539 123549 123564TGTCTCATGCCTTATA T_(ks)G_(es)T_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m) 20 2803 C_(ds)^(m)C_(ds)T_(ds)T_(es)A_(es)T_(ks)A_(k) 1198715 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(es)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds) 33 2804 T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(es)T_(es)T_(ks)A_(k) 1198716 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(es)T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 27 2805 A_(ds)T_(ds)G_(ds) ^(m)C_(es) ^(m)C_(es)T_(ks)T_(k)1198717 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(es)A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 41 443C_(ds)A_(ds)T_(ds)G_(es) ^(m)C_(es) ^(m)C_(ks)T_(k) 1198718 2529 2544123554 123569 GAAATTGTCTCATGCCG_(ks)A_(es)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 92800 C_(ds)A_(ds)T_(es)G_(es) ^(m)C_(ks) ^(m)C_(k) 1198719 2530 2545123555 123570 GGAAATTGTCTCATGCG_(ks)G_(es)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 142806 T_(ds) ^(m)C_(ds)A_(es)T_(es)G_(ks) ^(m)C_(k) 1198720 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(es)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 212807 C_(ds)T_(ds) ^(m)C_(es)A_(es)T_(ks)G_(k) 1198721 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(es)G_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 48 2808T_(ds) ^(m)C_(ds)T_(es) ^(m)C_(es)A_(ks)T_(k) 1198722 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(es)A_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 48 656T_(ds)G_(ds)T_(es) ^(m)C_(es)T_(ks) ^(m)C_(k) 1198723 2560 2575 123585123600 AGTATGTGGCAATAATA_(ks)G_(es)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) 572809 A_(ds)A_(ds)T_(es)A_(es)A_(ks)T_(k) 1198724 2562 2577 123587 123602AGAGTATGTGGCAATAA_(ks)G_(es)A_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 16 2810G_(ds) ^(m)C_(ds)A_(es)A_(es)T_(ks)A_(k) 1198725 2563 2578 123588 123603TAGAGTATGTGGCAATT_(ks)A_(es)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 23 2811G_(ds)G_(ds) ^(m)C_(es)A_(es)A_(ks)T_(k) 1198726 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(es)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 28 963T_(ds)G_(ds)G_(es) ^(m)C_(es)A_(ks)A_(k) 1198727 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(es)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 19 810G_(ds)T_(ds)G_(es)G_(es) ^(m)C_(ks)A_(k) 1198728 2566 2581 123591 123606TATTAGAGTATGTGGCT_(ks)A_(es)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 17 2812T_(ds)G_(ds)T_(es)G_(es)G_(ks) ^(m)C_(k) 1198729 2567 2582 123592 123607ATATTAGAGTATGTGGA_(ks)T_(es)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 21 2813A_(ds)T_(ds)G_(es)T_(es)G_(ks)G_(k) 1198730 2568 2583 123593 123608TATATTAGAGTATGTGT_(ks)A_(es)T_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 57 2814T_(ds)A_(ds)T_(es)G_(es)T_(ks)G_(k) 1198731 2570 2585 123595 123610TCTATATTAGAGTATG T_(ks)^(m)C_(es)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 59 887A_(ds)G_(ds)T_(es)A_(es)T_(ks)G_(k) 1198732 4436 4451 125461 125476TATAACTGGGCAAATT T_(ks)A_(es)T_(ks)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m) 86 2815C_(ds)A_(ds)A_(es)A_(es)T_(ks)T_(k) 1198741 4595 4610 125620 125635TTACATTAGGAACAAG T_(ks)T_(es)A_(ks)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 60 2817 A_(ds)A_(ds)^(m)C_(es)A_(es)A_(ks)G_(k) 1198742 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(es)T_(ks)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 143 2818 G_(ds)G_(ds)A_(es)A_(es)^(m)C_(ks)A_(k) 1198743 4598 4613 125623 125638 CTTTTACATTAGGAAC^(m)C_(ks)T_(es)T_(ks)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) 86 1124T_(ds)A_(ds)G_(ds)G_(es)A_(es)A_(ks) ^(m)C_(k) 1198744 4599 4614 125624125639 ACTTTTACATTAGGAA A_(ks) ^(m)C_(es)T_(ks)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 66 2819 T_(ds)T_(ds)A_(ds)G_(es)G_(es)A_(ks)A_(k)1198745 4600 4615 125625 125640 CACTTTTACATTAGGA ^(m)C_(ks)A_(es)^(m)C_(ks)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 57 1200A_(ds)T_(ds)T_(ds)A_(es)G_(es)G_(ks)A_(k) 1198746 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks) ^(m)C_(es)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 7 1276^(m)C_(ds)A_(ds)T_(ds)T_(es)A_(es)G_(ks)G_(k) 1198747 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G_(es) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 38 2820 A_(ds)^(m)C_(ds)A_(ds)T_(es)T_(es)A_(ks)G_(k) 1198748 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(es)G_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 81 2821 T_(ds)A_(ds)^(m)C_(ds)A_(es)T_(es)T_(ks)A_(k) 1198749 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(es)A_(ks)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 73 2822 T_(ds)T_(ds)T_(ds)A_(es) ^(m)C_(es)A_(ks)T_(k)1198750 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(es)A_(ks)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 32 2823G_(ds)A_(ds)A_(ds)A_(es) ^(m)C_(es)T_(ks) ^(m)C_(k) 1198751 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(es)G_(ks)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 762824 T_(ds)G_(ds)A_(es)A_(es)A_(ks) ^(m)C_(k) 1198752 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(es)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 1112825 C_(ds)T_(ds)G_(es)A_(es)A_(ks)A_(k) 1198753 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(es)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 58 2826T_(ds) ^(m)C_(ds)T_(es)G_(es)A_(ks)A_(k) 1198754 4800 4815 125825 125840GCTTTGGAAGATCTGA G_(ks)^(m)C_(es)T_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 23 2044A_(ds)T_(ds) ^(m)C_(es)T_(es)G_(ks)A_(k) 1198755 4801 4816 125826 125841TGCTTTGGAAGATCTG T_(ks)G_(es)^(m)C_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 32 2121G_(ds)A_(ds)T_(es) ^(m)C_(es)T_(ks)G_(k) 1198756 4802 4817 125827 125842GTGCTTTGGAAGATCT G_(ks)T_(es)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) 50 2827A_(ds)G_(ds)A_(es)T_(es) ^(m)C_(ks)T_(k) 1198757 4803 4818 125828 125843AGTGCTTTGGAAGATC A_(ks)G_(es)T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 4 2828A_(ds)A_(ds)G_(es)A_(es)T_(ks) ^(m)C_(k) 1198758 4805 4820 125830 125845ATAGTGCTTTGGAAGA A_(ks)T_(es)A_(ks)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 47 2829 G_(ds)G_(ds)A_(es)A_(es)G_(ks)A_(k)1198759 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(es)G_(ks)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) 27 2830G_(ds)G_(ds)T_(ds)T_(es)T_(es)T_(ks)T_(k) 1198760 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(es)A_(ks)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 91 2831 T_(ds)G_(ds)G_(es)T_(es)T_(ks)T_(k) 1198761 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(es)T_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 422832 A_(ds)T_(ds)G_(es)G_(es)T_(ks)T_(k) 1198762 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(es)T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)30 2833C_(ds)A_(ds)T_(es)G_(es)G_(ks)T_(k) 1198763 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(es)T_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 26 2834G_(ds) ^(m)C_(ds)A_(es)T_(es)G_(ks)G_(k) 1198764 N/A N/A 94735 94750AGATTTAGGATGCATGA_(ks)G_(es)A_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 28 2835T_(ds)G_(ds) ^(m)C_(es)A_(es)T_(ks)G_(k) 1198765 N/A N/A 94736 94751CAGATTTAGGATGCAT^(m)C_(ks)A_(es)A_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 23 2836A_(ds)T_(ds)G_(es) ^(m)C_(es)A_(ks)T_(k) 1198766 N/A N/A 94737 94752TCAGATTTAGGATGCA T_(ks)^(m)C_(es)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 19 2837G_(ds)A_(ds)T_(es)G_(es) ^(m)C_(ks)A_(k) 1198767 N/A N/A 94739 94754ATTCAGATTTAGGATG A_(ks)T_(es)T_(ks)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds) 65 2838A_(ds)G_(ds)G_(es)A_(es)T_(ks)G_(k) 1198777 N/A N/A 117325 117340ATTGCAATCTGTCTGA A_(ks)T_(es)T_(ks)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 84 2843 T_(ds)G_(ds)T_(ds) ^(m)C_(es)T_(es)G_(ks)A_(k)1198778 N/A N/A 117327 117342 ATATTGCAATCTGTCTA_(ks)T_(es)A_(ks)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m)55 2844 C_(ds)T_(ds)G_(es)T_(es) ^(m)C_(ks)T_(k) 1198779 N/A N/A 117328117343 AATATTGCAATCTGTC A_(ks)A_(es)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds) 49 2845 T_(ds) ^(m)C_(ds)T_(es)G_(es)T_(ks)^(m)C_(k) 1198780 N/A N/A 117329 117344 TAATATTGCAATCTGTT_(ks)A_(es)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 802846 A_(ds)T_(ds) ^(m)C_(es)T_(es)G_(ks)T_(k) 1198781 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(es)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 251404 A_(ds)A_(ds)T_(es) ^(m)C_(es)T_(ks)G_(k) 1198782 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(es)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 612847 C_(ds)A_(ds)A_(es)T_(es) ^(m)C_(ks)T_(k) 1198783 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(es)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 78 2848G_(ds) ^(m)C_(ds)A_(es)A_(es)T_(ks) ^(m)C_(k) 1198784 N/A N/A 117333117348 TATGTAATATTGCAATT_(ks)A_(es)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 94 2849T_(ds)G_(ds) ^(m)C_(es)A_(es)A_(ks)T_(k) 1198785 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(es)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 86 2850A_(ds)T_(ds)T_(es)G_(es) ^(m)C_(ks)A_(k) 1198795 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(es)A_(ks)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 43 2851 C_(ds) ^(m)C_(ds)A_(ds)G_(es)A_(es)T_(ks)T_(k)1198796 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(es)T_(ks)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 322852 C_(ds) ^(m)C_(ds) ^(m)C_(es)A_(es)G_(ks)A_(k) 1198797 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(es)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 31 2853T_(ds) ^(m)C_(ds) ^(m)C_(es) ^(m)C_(es)A_(ks)G_(k) 1198798 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(es)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 38 2854T_(ds)T_(ds) ^(m)C_(es) ^(m)C_(es) ^(m)C_(ks)A_(k) 1198799 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(es)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 18 1101G_(ds)T_(ds)T_(ds)T_(es) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(k) 1198800 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(es)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 47 2855G_(ds)G_(ds)T_(ds)T_(es)T_(es) ^(m)C_(ks) ^(m)C_(k) 1198801 N/A N/A119674 119689 GACTAAGTAAGGTTTC G_(ks)A_(es)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 47 2856A_(ds)G_(ds)G_(ds)T_(es)T_(es)T_(ks) ^(m)C_(k) 1198802 N/A N/A 119675119690 AGACTAAGTAAGGTTT A_(ks)G_(es)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 83 2857A_(ds)A_(ds)G_(ds)G_(es)T_(es)T_(ks)T_(k) 1198803 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(es)A_(ks)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 62 2858T_(ds)A_(ds)A_(es)G_(es)G_(ks)T_(k)

TABLE 41Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ ID ID SEQ SEQ NO: 1 NO: 1 ID NO: ID NO: YAP1 SEQ Compound StartStop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5' to 3')CHEMISTRY NOTATION UTC) NO 715487 3630 3645 124655 124670ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 28 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 14 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 12 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1198628 2524 2539 123549 123564 TGTCTCATGCCTTATA T_(ks)G 272803 C_(ds) ^(m)C_(ds)T_(ds)T_(ks)A_(es)T_(ks)A_(e) 1198629 2526 2541123551 123566 ATTGTCTCATGCCTTA A_(ks)T_(ks)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds) 22 2804 T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ks)T_(es)T_(ks)A_(e) 1198630 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 37 2805 A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(e)1198631 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 53 443C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(es) ^(m)C_(ks)T_(e) 1198632 2529 2544123554 123569 GAAATTGTCTCATGCCG_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)21 2800 C_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks) ^(m)C_(e) 1198633 2530 2545123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 46 2806C_(ds)T_(ds) ^(m)C_(ds)A_(ks)T_(es)G_(ks) ^(m)C_(e) 1198634 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 342807 C_(ds)T_(ds) ^(m)C_(ks)A_(es)T_(ks)G_(e) 1198635 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 57 2808T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)A_(ks)T_(e) 1198636 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 41 656T_(ds)G_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e) 1198637 2560 2575 123585123600 AGTATGTGGCAATAATA_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m) 64 2809C_(ds)A_(ds)A_(ds)T_(ks)A_(es)A_(ks)T_(e) 1198638 2562 2577 123587123602 AGAGTATGTGGCAATAA_(ks)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 18 2810G_(ds) ^(m)C_(ds)A_(ks)A_(es)T_(ks)A_(e) 1198639 2563 2578 123588 123603TAGAGTATGTGGCAATT_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 32 2811G_(ds)G_(ds) ^(m)C_(ks)A_(es)A_(ks)T_(e) 1198640 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 26 963T_(ds)G_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(e) 1198641 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 15 810G_(ds)T_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(e) 1198642 2566 2581 123591 123606TATTAGAGTATGTGGCT_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 19 2812T_(ds)G_(ds)T_(ks)G_(es)G_(ks) ^(m)C_(e) 1198643 2567 2582 123592 123607ATATTAGAGTATGTGGA_(ks)T_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 25 2813A_(ds)T_(ds)G_(ks)T_(es)G_(ks)G_(e) 1198644 2568 2583 123593 123608TATATTAGAGTATGTGT_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 73 2814T_(ds)A_(ds)T_(ks)G_(es)T_(ks)G_(e) 1198645 2570 2585 123595 123610TCTATATTAGAGTATG T_(ks)^(m)C_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 73 887A_(ds)G_(ds)T_(ks)A_(es)T_(ks)G_(e) 1198651 4595 4610 125620 125635TTACATTAGGAACAAG T_(ks)T_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 94 2817 A_(ds)A_(ds)^(m)C_(ks)A_(es)A_(ks)G_(e) 1198652 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ks)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 68 2818 G_(ds)G_(ds)A_(ks)A_(es)^(m)C_(ks)A_(e) 1198653 4598 4613 125623 125638 CTTTTACATTAGGAAC^(m)C_(ks)T_(ks)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) 64 1124T_(ds)A_(ds)G_(ds)G_(ks)A_(es)A_(ks) ^(m)C_(e) 1198654 4599 4614 125624125639 ACTTTTACATTAGGAA A_(ks) ^(m)C_(ks)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 91 2819 T_(ds)T_(ds)A_(ds)G_(ks)G_(es)A_(ks)A_(e)1198655 4600 4615 125625 125640 CACTTTTACATTAGGA ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 30 1200A_(ds)T_(ds)T_(ds)A_(ks)G_(es)G_(ks)A_(e) 1198656 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 11 1276C_(ds)A_(ds)T_(ds)T_(ks)A_(es)G_(ks)G_(e) 1198657 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 95 2820 A_(ds)^(m)C_(ds)A_(ds)T_(ks)T_(es)A_(ks)G_(e) 1198658 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(ks)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 62 2821 T_(ds)A_(ds)^(m)C_(ds)A_(ks)T_(es)T_(ks)A_(e) 1198659 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 58 2822 T_(ds)T_(ds)T_(ds)A_(ks) ^(m)C_(es)A_(ks)T_(e)1198660 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 66 2823G_(ds)A_(ds)A_(ds)A_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e) 1198661 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 111 2824C_(ds)T_(ds)G_(ds)A_(ks)A_(es)A_(ks) ^(m)C_(e) 1198662 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 832825 C_(ds)T_(ds)G_(ks)A_(es)A_(ks)A_(e) 1198663 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 76 2826A_(ds)T_(ds) ^(m)C_(ds)T_(ks)G_(es)A_(ks)A_(e) 1198664 4800 4815 125825125840 GCTTTGGAAGATCTGA G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 18 2044G_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(e) 1198665 4801 4816 125826125841 TGCTTTGGAAGATCTG T_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 38 2121G_(ds)A_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(e) 1198666 4802 4817 125827 125842GTGCTTTGGAAGATCT G_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(d s)G_(ds)A_(ds) 44 2827A_(ds)G_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(e) 1198667 4803 4818 125828 125843AGTGCTTTGGAAGATC A_(ks)G_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 40 2828A_(ds)A_(ds)G_(ks)A_(es)T_(ks) ^(m)C_(e) 1198668 4805 4820 125830 125845ATAGTGCTTTGGAAGA A_(ks)T_(ks)A_(ds)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 72 2829 G_(ds)G_(ds)A_(ks)A_(es)G_(ks)A_(e)1198669 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ks)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) 61 2830G_(ds)G_(ds)T_(ds)T_(ks)T_(es)T_(ks)T_(e) 1198670 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds) 55 2831 A_(ds)T_(ds)G_(ds)G_(ks)T_(es)T_(ks)T_(e) 1198671 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 262832 A_(ds)T_(ds)G_(ks)G_(es)T_(ks)T_(e) 1198672 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 412833 C_(ds)A_(ds)T_(ks)G_(es)G_(ks)T_(e) 1198673 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 10 2834G_(ds) ^(m)C_(ds)A_(ks)T_(es)G_(ks)G_(e) 1198674 N/A N/A 94735 94750AGATTTAGGATGCATGA_(ks)G_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 21 2835T_(ds)G_(ds) ^(m)C_(ks)A_(es)T_(ks)G_(e) 1198675 N/A N/A 94736 94751CAGATTTAGGATGCAT^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 35 2836G_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(es)A_(ks)T_(e) 1198676 N/A N/A 9473794752 TCAGATTTAGGATGCA T_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 52 2837G_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks)A_(e) 1198677 N/A N/A 94739 94754ATTCAGATTTAGGATG A_(ks)T_(ks)T_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds) 87 2838A_(ds)G_(ds)G_(ks)A_(es)T_(ks)G_(e) 1198687 N/A N/A 117325 117340ATTGCAATCTGTCTGA A_(ks)T_(ks)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 55 2843 T_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(e)1198688 N/A N/A 117327 117342 ATATTGCAATCTGTCTA_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m)48 2844 C_(ds)T_(ds)G_(ks)T_(es) ^(m)C_(ks)T_(e) 1198689 N/A N/A 117328117343 AATATTGCAATCTGTC A_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 91 2845 A_(ds)T_(ds) ^(m)C_(ds)T_(ks)G_(es)T_(ks)^(m)C_(e) 1198690 N/A N/A 117329 117344 TAATATTGCAATCTGTT_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 642846 A_(ds)T_(ds) ^(m)C_(ks)T_(es)G_(ks)T_(e) 1198691 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 381404 A_(ds)A_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(e) 1198692 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 1202847 C_(ds)A_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(e) 1198733 4438 4453 125463125478 GGTATAACTGGGCAAA G_(ks)G_(es)T_(ks)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds) 47 1427 G_(ds)G_(ds) ^(m)C_(es)A_(es)A_(ks)A_(k)1198734 4439 4454 125464 125479 AGGTATAACTGGGCAAA_(ks)G_(es)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) 29 905G_(ds)G_(ds)G_(es) ^(m)C_(es)A_(ks)A_(k) 1198735 4440 4455 125465 125480GAGGTATAACTGGGCA G_(ks)A_(es)G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m) 34 1503 C_(ds)T_(ds)G_(ds)G_(es)G_(es) ^(m)C_(ks)A_(k) 1198736 44414456 125466 125481 TGAGGTATAACTGGGCT_(ks)G_(es)A_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 201580 C_(ds)T_(ds)G_(es)G_(es)G_(ks) ^(m)C_(k) 1198737 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(es)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 24 2801A_(ds)A_(ds) ^(m)C_(ds)T_(es)G_(es)G_(ks)G_(k) 1198738 4443 4458 125468125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(es)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 38 392A_(ds)A_(ds) ^(m)C_(es)T_(es)G_(ks)G_(k) 1198739 4444 4459 125469 125484CACTGAGGTATAACTG ^(m)C_(ks)A_(es)^(m)C_(ks)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 94 2802A_(ds)T_(ds)A_(ds)A_(es) ^(m)C_(es)T_(ks)G_(k) 1198740 4446 4461 125471125486 AACACTGAGGTATAAC A_(ks)AmC_(ks)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 39 2816G_(ds)T_(ds)A_(ds)T_(es)A_(es)A_(ks) ^(m)C_(k) 1198768 N/A N/A 115903115918 ATATGGTTTTGTGTGTA_(ks)T_(es)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 61 2839G_(ds)T_(ds)G_(es)T_(es)G_(ks)T_(k) 1198769 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(es)A_(ks)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 77 2840T_(ds)T_(ds)G_(es)T_(es)G_(ks)T_(k) 1198770 N/A N/A 115906 115921CTTATATGGTTTTGTG^(m)C_(ks)T_(es)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 40 2788T_(ds)T_(ds)T_(ds)T_(es)G_(es)T_(ks)G_(k) 1198771 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks)^(m)C_(es)T_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 85 2841T_(ds)T_(ds)T_(es)T_(es)G_(ks)T_(k) 1198772 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(es)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 41 2842G_(ds)G_(ds)T_(ds)T_(es)T_(es)T_(ks)G_(k) 1198773 N/A N/A 115909 115924ACTCTTATATGGTTTT A_(ks) ^(m)C_(es)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 58 2859T_(ds)G_(ds)G_(ds)T_(es)T_(es)T_(ks)T_(k) 1198774 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(es) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 106 2860A_(ds)T_(ds)G_(ds)G_(es)T_(es)T_(ks)T_(k) 1198775 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(es)A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 113 2861T_(ds)A_(ds)T_(ds)G_(es)G_(es)T_(ks)T_(k) 1198776 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(es) ^(m+lC) _(ks)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds) 57 2862 T_(ds)A_(ds)T_(ds)A_(es)T_(es)G_(ks)G_(k)1198786 N/A N/A 117755 117770 TGTATGTCAGAAGAGTT_(ks)G_(es)T_(ks)A_(ds)T_(ds)G_(ds)T_(dshu m)C_(ds)A_(ds)G_(ds) 16 2863A_(ds)A_(ds)G_(es)A_(es)G_(ks)T_(k) 1198787 N/A N/A 117757 117772AGTGTATGTCAGAAGA A_(ks)G_(es)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds) 9 2864 A_(ds)G_(ds)A_(es)A_(es)G_(ks)A_(k) 1198788 N/A N/A117758 117773 AAGTGTATGTCAGAAGA_(ks)A_(es)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 172865 C_(ds)A_(ds)G_(es)A_(es)A_(ks)G_(k) 1198789 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(es)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 22 2866T_(ds) ^(m)C_(ds)A_(es)G_(es)A_(ks)A_(k) 1198790 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(es)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 27 2867G_(ds)T_(ds) ^(m)C_(es)A_(es)G_(ks)A_(k) 1198791 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks)A T_(es)A_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 39 2868T_(ds)G_(ds)T_(es) ^(m)C_(es)A_(ks)G_(k) 1198792 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(es)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 48 2869A_(ds)T_(ds)G_(es)T_(es) ^(m)C_(ks)A_(k) 1198793 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(es)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 34 1634G_(ds)T_(ds)A_(ds)T_(es)G_(es)T_(ks) ^(m)C_(k) 1198794 N/A N/A 117765117780 AACTTTAAAGTGTATG A_(ks)A_(es)^(m)C_(ks)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) 74 2870T_(ds)G_(ds)T_(es)A_(es)T_(ks)G_(k)

TABLE 42Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ ID ID SEQ SEQ NO: 1 NO: 1 ID NO: ID NO: YAP1 SEQ Compound StartStop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5' to 3')CHEMISTRY NOTATION UTC) NO 715487 3630 3645 124655 124670ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 29 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 15 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 11 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1095463 4443 4458 125468 125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds) 37 392T_(ds)A_(ds)A_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(e) 1095481 4441 4456 125466125481 TGAGGTATAACTGGGCT_(ks)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 211580 C_(ds)T_(ds)G_(ks)G_(es)G_(ks) ^(m)C_(e) 1095482 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 72 2801A_(ds)A_(ds) ^(m)C_(ds)T_(ks)G_(es)G_(ks)G_(e) 1095483 4444 4459 125469125484 CACTGAGGTATAACTG ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 101 2802A_(ds)T_(ds)A_(ds)A_(ks) ^(m)C_(es)T_(ks)G_(e) 1198198 2524 2539 123549123564 TGTCTCATGCCTTATA T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m) 29 2803 C_(ds)^(m)C_(ds)T_(es)T_(es)A_(es)T_(ks)A_(k) 1198199 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds) 38 2804 T_(ds)G_(ds) ^(m)C_(es)^(m)C_(es)T_(es)T_(ks)A_(k) 1198200 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 49 2805 A_(ds)T_(ds)G_(es) ^(m)C_(es) ^(m)C_(es)T_(ks)T_(k)1198201 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 34 443C_(ds)A_(ds)T_(es)G_(es) ^(m)C_(es) ^(m)C_(ks)T_(k) 1198202 2529 2544123554 123569 GAAATTGTCTCATGCCG_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)14 2800 C_(ds)A_(es)T_(es)G_(es) ^(m)C_(ks) ^(m)C_(k) 1198203 2530 2545123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 19 2806C_(ds)T_(ds) ^(m)C_(es)A_(es)T_(es)G_(ks) ^(m)C_(k) 1198204 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 312807 C_(ds)T_(es) ^(m)C_(es)A_(es)T_(ks)G_(k) 1198205 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 64 2808T_(ds) ^(m)C_(es)T_(es) ^(m)C_(es)A_(ks)T_(k) 1198206 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 43 656T_(ds)G_(es)T_(es) ^(m)C_(es)T_(ks) ^(m)C_(k) 1198207 2560 2575 123585123600 AGTATGTGGCAATAATA_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m) 91 2809C_(ds)A_(ds)A_(es)T_(es)A_(es)A_(ks)T_(k) 1198208 2562 2577 123587123602 AGAGTATGTGGCAATAA_(ks)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 25 2810G_(ds) ^(m)C_(es)A_(es)A_(es)T_(ks)A_(k) 1198209 2563 2578 123588 123603TAGAGTATGTGGCAATT_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 45 2811G_(ds)G_(es) ^(m)C_(es)A_(es)A_(ks)T_(k) 1198210 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 28 963T_(ds)G_(es)G_(es) ^(m)C_(es)A_(ks)A_(k) 1198211 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 19 810G_(ds)T_(es)G_(es)G_(es) ^(m)C_(ks)A_(k) 1198212 2566 2581 123591 123606TATTAGAGTATGTGGCT_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 17 2812T_(ds)G_(es)T_(es)G_(es)G_(ks) ^(m)C_(k) 1198213 2567 2582 123592 123607ATATTAGAGTATGTGGA_(ks)T_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 16 2813A_(ds)T_(es)G_(es)T_(es)G_(ks)G_(k) 1198214 2568 2583 123593 123608TATATTAGAGTATGTGT_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 91 2814T_(ds)A_(es)T_(es)G_(es)T_(ks)G_(k) 1198215 2570 2585 123595 123610TCTATATTAGAGTATG T_(ks)^(m)C_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 120 887A_(ds)G_(es)T_(es)A_(es)T_(ks)G_(k) 1198221 4595 4610 125620 125635TTACATTAGGAACAAG T_(ks)T_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 95 2817 A_(ds)A_(es)^(m)C_(es)A_(es)A_(ks)G_(k) 1198222 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ks)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 87 2818 G_(ds)G_(es)A_(es)A_(es)^(m)C_(ks)A_(k) 1198223 4598 4613 125623 125638 CTTTTACATTAGGAAC^(m)C_(ks)T_(ks)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) 94 1124T_(ds)A_(ds)G_(es)G_(es)A_(es)A_(ks) ^(m)C_(k) 1198224 4599 4614 125624125639 ACTTTTACATTAGGAA A_(ks) ^(m)C_(ks)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 74 2819 T_(ds)T_(ds)A_(es)G_(es)G_(es)A_(ks)A_(k)1198225 4600 4615 125625 125640 CACTTTTACATTAGGA ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 67 1200A_(ds)T_(ds)T_(es)A_(es)G_(es)G_(ks)A_(k) 1198226 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 23 1276C_(ds)A_(ds)T_(es)T_(es)A_(es)G_(ks)G_(k) 1198227 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 104 2820 A_(ds)^(m)C_(ds)A_(es)T_(es)T_(es)A_(ks)G_(k) 1198228 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(ks)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 54 2821 T_(ds)A_(ds)^(m)C_(es)A_(es)T_(es)T_(ks)A_(k) 1198229 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 80 2822 T_(ds)T_(ds)T_(es)A_(es) ^(m)C_(es)A_(ks)T_(k)1198230 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 81 2823G_(ds)A_(ds)A_(es)A_(es) ^(m)C_(es)T_(ks) ^(m)C_(k) 1198231 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 73 2824C_(ds)T_(ds)G_(es)A_(es)A_(es)A_(ks) ^(m)C_(k) 1198232 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 922825 C_(ds)T_(es)G_(es)A_(es)A_(ks)A_(k) 1198233 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 49 2826A_(ds)T_(ds) ^(m)C_(es)T_(es)G_(es)A_(ks)A_(k) 1198234 4800 4815 125825125840 GCTTTGGAAGATCTGA G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 45 2044G_(ds)A_(ds)T_(es) ^(m)C_(es)T_(es)G_(ks)A_(k) 1198235 4801 4816 125826125841 TGCTTTGGAAGATCTG T_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 49 2121G_(ds)A_(es)T_(es) ^(m)C_(es)T_(ks)G_(k) 1198236 4802 4817 125827 125842GTGCTTTGGAAGATCT G_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) 24 2827A_(ds)G_(es)A_(es)T_(es) ^(m)C_(ks)T_(k) 1198237 4803 4818 125828 125843AGTGCTTTGGAAGATC A_(ks)G_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 51 2828G_(ds)A_(ds)A_(es)G_(es)T_(ks) ^(m)C_(k) 1198238 4805 4820 125830 125845ATAGTGCTTTGGAAGA A_(ks)T_(ks)A_(ds)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 88 2829 G_(ds)G_(es)A_(es)A_(es)G_(ks)A_(k)1198239 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ks)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) 39 2830G_(ds)G_(ds)T_(es)T_(es)T_(es)T_(ks)T_(k) 1198240 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds) 43 2831 A_(ds)T_(ds)G_(es)G_(es)T_(es)T_(ks)T_(k) 11986464436 4451 125461 125476 TATAACTGGGCAAATT T_(ks)A_(ks)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds) 80 2815 G_(ds)^(m)C_(ds)A_(ds)A_(ks)A_(es)T_(ks)T_(e) 1198647 4438 4453 125463 125478GGTATAACTGGGCAAA G_(ks)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds) 47 1427 G_(ds)G_(ds)G_(ds) ^(m)C_(ks)A_(es)A_(ks)A_(e)1198648 4439 4454 125464 125479 AGGTATAACTGGGCAAA_(ks)G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) 43 905T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(e) 1198649 4440 4455 125465125480 GAGGTATAACTGGGCAG_(ks)A_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 27 1503C_(ds)T_(ds)G_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(e) 1198650 4446 4461 125471125486 AACACTGAGGTATAAC A_(ks)A_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 88 2816G_(ds)T_(ds)A_(ds)T_(Tks+lAes)A_(ks) ^(m)C_(e) 1198678 N/A N/A 115903115918 ATATGGTTTTGTGTGTA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 58 2839G_(ds)T_(ds)G_(ks)T_(es)G_(ks)T_(e) 1198679 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 54 2840T_(ds)T_(ds)G_(ks)T_(es)G_(ks)T_(e) 1198680 N/A N/A 115906 115921CTTATATGGTTTTGTG^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 28 2788T_(ds)T_(ds)T_(ks)G_(es)T_(ks)G_(e) 1198681 N/A N/A 115907 115922TCTTATATGGTTTTGTT_(ks)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 54 2841T_(ds)T_(ds)T_(ks)T_(es)G_(ks)T_(e) 1198682 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 25 2842G_(ds)G_(ds)T_(ds)T_(ks)T_(es)T_(ks)G_(e) 1198683 N/A N/A 115909 115924ACTCTTATATGGTTTT A_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 27 2859T_(ds)G_(ds)G_(ds)T_(ks)T_(es)T_(ks)T_(e) 1198684 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 75 2860A_(ds)T_(ds)G_(ds)G_(ks)T_(es)T_(ks)T_(e) 1198685 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(ks)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 70 2861T_(ds)A_(ds)T_(ds)G_(ks)G_(es)T_(ks)T_(e) 1198686 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(ks) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds) 78 2862 T_(ds)A_(ds)T_(ds)A_(ks)T_(es)G_(ks)G_(e)1198693 N/A N/A 117332 117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 92 2848G_(ds) ^(m)C_(ds)A_(ks)A_(es)T_(ks) ^(m)C_(e) 1198694 N/A N/A 117333117348 TATGTAATATTGCAATT_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 110 2849T_(ds)G_(ds) ^(m)C_(ks)A_(es)A_(ks)T_(e) 1198695 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 75 2850A_(ds)T_(ds)T_(ks)G_(es) ^(m)C_(ks)A_(e) 1198696 N/A N/A 117755 117770TGTATGTCAGAAGAGT T_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds)G_(ds) 12 2863 A_(ds)A_(ds)G_(ks)A_(es)G_(ks)T_(e)1198697 N/A N/A 117757 117772 AGTGTATGTCAGAAGAA_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 122864 A_(ds)G_(ds)A_(ks)A_(es)G_(ks)A_(e) 1198698 N/A N/A 117758 117773AAGTGTATGTCAGAAGA_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 122865 C_(ds)A_(ds)G_(ks)A_(es)A_(ks)G_(e) 1198699 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 30 2866T_(ds) ^(m)C_(ds)A_(ks)G_(es)A_(ks)A_(e) 1198700 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 26 2867G_(ds)T_(ds) ^(m)C_(ks)A_(es)G_(ks)A_(e) 1198701 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 46 2868T_(ds)G_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(e) 1198702 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 74 2869A_(ds)T_(ds)G_(ks)T_(es) ^(m)C_(ks)A_(e) 1198703 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 42 1634T_(ds)A_(ds)T_(ks)G_(es)T_(ks) ^(m)C_(e) 1198704 N/A N/A 117765 117780AACTTTAAAGTGTATG A_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) 72 2870G_(ds)T_(ds)G_(ds)T_(ks)A_(es)T_(ks)G_(e) 1198705 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(ks)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 70 2851 C_(ds) ^(m)C_(ds)A_(ds)G_(ks)A_(es)T_(ks)T_(e)1198706 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 392852 C_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)G_(ks)A_(e) 1198707 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 31 2853T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(e) 1198708 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 34 2854T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(e) 1198709 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 29 1101G_(ds)T_(ds)T_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(e) 1198710 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 51 2855G_(ds)G_(ds)T_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 1198711 N/A N/A119674 119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 60 2856A_(ds)G_(ds)G_(ds)T_(ks)T_(es)T_(ks) ^(m)C_(e) 1198712 N/A N/A 119675119690 AGACTAAGTAAGGTTT A_(ks)G_(ks)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 110 2857A_(ds)A_(ds)G_(ds)G_(ks)T_(es)T_(ks)T_(e) 1198713 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds) 62 2858G_(ds)T_(ds)A_(ds)A_(ks)G_(es)G_(ks)T_(e)

TABLE 43Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ ID ID SEQ SEQ NO: 1 NO: 1 ID NO: ID NO: YAP1 SEQ Compound StartStop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5' to 3')CHEMISTRY NOTATION UTC) NO 715487 3630 3645 124655 124670ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 25 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 14 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds) 11 2800 T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1095575 4443 4458 125468 125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds) 55 392T_(ds)A_(ds)A_(es) ^(m)C_(es)T_(es)G_(ks)G_(k) 1095593 4441 4456 125466125481 TGAGGTATAACTGGGCT_(ks)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 161580 C_(ds)T_(es)G_(es)G_(es)G_(ks) ^(m)C_(k) 1095594 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 27 2801A_(ds)A_(ds) ^(m)C_(es)T_(es)G_(es)G_(ks)G_(k) 1095595 4444 4459 125469125484 CACTGAGGTATAACTG ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 63 2802A_(ds)T_(ds)A_(es)A_(es) ^(m)C_(es)T_(ks)G_(k) 1198216 4436 4451 125461125476 TATAACTGGGCAAATT T_(ks)A_(ks)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds) 89 2815 G_(ds)^(m)C_(ds)A_(es)A_(es)A_(es)T_(ks)T_(k) 1198217 4438 4453 125463 125478GGTATAACTGGGCAAA G_(ks)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds) 57 1427 G_(ds)G_(ds)G_(es) ^(m)C_(es)A_(es)A_(ks)A_(k)1198218 4439 4454 125464 125479 AGGTATAACTGGGCAAA_(ks)G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) 40 905T_(ds)G_(ds)G_(es)G_(es) ^(m)C_(es)A_(ks)A_(k) 1198219 4440 4455 125465125480 GAGGTATAACTGGGCAG_(ks)A_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 22 1503C_(ds)T_(ds)G_(es)G_(es)G_(es) ^(m)C_(ks)A_(k) 1198220 4446 4461 125471125486 AACACTGAGGTATAAC A_(ks)A_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 89 2816G_(ds)T_(ds)A_(es)T_(es)A_(es)A_(ks) ^(m)C_(k) 1198241 N/A N/A 9473294747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 32 2832C_(ds)A_(ds)T_(es)G_(es)G_(es)T_(ks)T_(k) 1198242 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 472833 C_(ds)A_(es)T_(es)G_(es)G_(ks)T_(k) 1198243 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 8 2834G_(ds) ^(m)C_(es)A_(es)T_(es)G_(ks)G_(k) 1198244 N/A N/A 94735 94750AGATTTAGGATGCATGA_(ks)G_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 24 2835T_(ds)G_(es) ^(m)C_(es)A_(es)T_(ks)G_(k) 1198245 N/A N/A 94736 94751CAGATTTAGGATGCAT^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 46 2836G_(ds)A_(ds)T_(es)G_(es) ^(m)C_(es)A_(ks)T_(k) 1198246 N/A N/A 9473794752 TCAGATTTAGGATGCA T_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds) 30 2837G_(ds)G_(ds)A_(es)T_(es)G_(es) ^(m)C_(ks)A_(k) 1198247 N/A N/A 9473994754 ATTCAGATTTAGGATG A_(ks)T_(ks)T_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds) 99 2838A_(ds)G_(es)G_(es)A_(es)T_(ks)G_(k) 1198248 N/A N/A 115903 115918ATATGGTTTTGTGTGTA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 64 2839G_(ds)T_(es)G_(es)T_(es)G_(ks)T_(k) 1198249 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 42 2840T_(ds)T_(es)G_(es)T_(es)G_(ks)T_(k) 1198250 N/A N/A 115906 115921CTTATATGGTTTTGTG^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 50 2788T_(ds)T_(es)T_(es)G_(es)T_(ks)G_(k) 1198251 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 83 2841T_(ds)T_(es)T_(es)T_(es)G_(ks)T_(k) 1198252 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 26 2842G_(ds)G_(ds)T_(es)T_(es)T_(es)T_(ks)G_(k) 1198253 N/A N/A 115909 115924ACTCTTATATGGTTTT A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 50 2859T_(ds)G_(ds)G_(es)T_(es)T_(es)T_(ks)T_(k) 119825 4 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 95 2860A_(ds)T_(ds)G_(es)G_(es)T_(es)T_(ks)T_(k) 1198255 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(ks)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 84 2861T_(ds)A_(ds)T_(es)G_(es)G_(es)T_(ks)T_(k) 1198256 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(ks) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds) 78 2862 T_(ds)A_(ds)T_(es)A_(es)T_(es)G_(ks)G_(k)1198257 N/A N/A 117325 117340 ATTGCAATCTGTCTGA A_(ks)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) 85 2843 T_(ds)G_(ds)T_(es)^(m)C_(es)T_(es)G_(ks)A_(k) 1198258 N/A N/A 117327 117342ATATTGCAATCTGTCT A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds) 52 2844 T_(ds) ^(m)C_(ds)T_(es)G_(es)T_(es)^(m)C_(ks)T_(k) 1198259 N/A N/A 117328 117343 AATATTGCAATCTGTCA_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 51 2845A_(ds)T_(ds) ^(m)C_(es)T_(es)G_(es)T_(ks) ^(m)C_(k) 1198260 N/A N/A117329 117344 TAATATTGCAATCTGTT_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 106 2846A_(ds)A_(ds)T_(es) ^(m)C_(es)T_(es)G_(ks)T_(k) 1198261 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 54 1404C_(ds)A_(ds)A_(es)T_(es) ^(m)C_(es)T_(ks)G_(k) 1198262 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 1142847 C_(ds)A_(es)A_(es)T_(es) ^(m)C_(ks)T_(k) 1198263 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 114 2848G_(ds) ^(m)C_(es)A_(es)A_(es)T_(ks) ^(m)C_(k) 1198264 N/A N/A 117333117348 TATGTAATATTGCAATT_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 73 2849T_(ds)G_(es) ^(m)C_(es)A_(es)A_(ks)T_(k) 1198265 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 111 2850A_(ds)T_(es)T_(es)G_(es) ^(m)C_(ks)A_(k) 1198266 N/A N/A 117755 117770TGTATGTCAGAAGAGT T_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds) 25 2863 G_(ds)A_(ds)A_(es)G_(es)A_(es)G_(ks)T_(k)1198267 N/A N/A 117757 117772 AGTGTATGTCAGAAGAA_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 7 2864C_(ds)A_(ds)G_(es)A_(es)A_(es)G_(ks)A_(k) 1198268 N/A N/A 117758 117773AAGTGTATGTCAGAAGA_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 112865 C_(ds)A_(es)G_(es)A_(es)A_(ks)G_(k) 1198269 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 58 2866T_(ds) ^(m)C_(es)A_(es)G_(es)A_(ks)A_(k) 1198270 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 52 2867G_(ds)T_(es) ^(m)C_(es)A_(es)G_(ks)A_(k) 1198271 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 44 2868T_(ds)G_(es)T_(es) ^(m)CesA_(ks)G_(k) 1198272 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 37 2869A_(ds)T_(es)G_(es)T_(es) ^(m)C_(ks)A_(k) 1198273 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 52 1634G_(ds)T_(ds)A_(es)T_(es)G_(es)T_(ks) ^(m)C_(k) 1198274 N/A N/A 117765117780 AACTTTAAAGTGTATG A_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) 69 2870G_(ds)T_(ds)G_(es)T_(es)A_(es)T_(ks)G_(k) 1198275 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(ks)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 52 2851 C_(ds) ^(m)C_(ds)A_(es)G_(es)A_(es)T_(ks)T_(k)1198276 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 522852 C_(ds) ^(m)C_(es) ^(m)C_(es)A_(es)G_(ks)A_(k) 1198277 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 32 2853T_(ds) ^(m)C_(es) ^(m)C_(es) ^(m)C_(es)A_(ks)G_(k) 1198278 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 43 2854T_(ds)T_(es) ^(m)C_(es) ^(m)C_(es) ^(m)C_(ks)A_(k) 1198279 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 43 1101G_(ds)T_(ds)T_(es)T_(es) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(k) 1198280 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 40 2855G_(ds)G_(ds)T_(es)T_(es)T_(es) ^(m)C_(ks) ^(m)C_(k) 1198281 N/A N/A119674 119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 71 2856A_(ds)G_(ds)G_(es)T_(es)T_(es)T_(ks) ^(m)C_(k) 1198282 N/A N/A 119675119690 AGACTAAGTAAGGTTT A_(ks)G_(ks)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 58 2857A_(ds)A_(ds)G_(es)G_(es)T_(es)T_(ks)T_(k) 1198283 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds) 99 2858G_(ds)T_(ds)A_(es)A_(es)G_(es)G_(ks)T_(k) 1198456 2524 2539 123549123564 TGTCTCATGCCTTATA T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m) 21 2803 C_(ds)^(m)C_(ds)T_(es)T_(ks)A_(es)T_(ks)A_(e) 1198457 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds) 18 2804 T_(ds)G_(ds) ^(m)C_(es)^(m)C_(ks)T_(es)T_(ks)A_(e) 1198458 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 30 2805 A_(ds)T_(ds)G_(es) ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(e)1198459 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 28 443C_(ds)A_(ds)T_(es)G_(ks) ^(m)C_(es) ^(m)C_(ks)T_(e) 1198460 2529 2544123554 123569 GAAATTGTCTCATGCCG_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 17 2800T_(ds) ^(m)C_(ds)A_(es)T_(ks)G_(es) ^(m)C_(ks) ^(m)C_(e) 1198461 25302545 123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 24 2806C_(ds)T_(ds) ^(m)C_(es)A_(ks)T_(es)G_(ks) ^(m)C_(e) 1198462 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 272807 C_(ds)T_(es) ^(m)C_(ks)A_(es)T_(ks)G_(e) 1198463 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 59 2808T_(ds) ^(m)C_(es)T_(ks) ^(m)C_(es)A_(ks)T_(e) 1198464 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 41 656T_(ds)G_(es)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e) 1198465 2560 2575 123585123600 AGTATGTGGCAATAATA_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m) 68 2809C_(ds)A_(ds)A_(es)T_(ks)A_(es)A_(ks)T_(e) 1198466 2562 2577 123587123602 AGAGTATGTGGCAATAA_(ks)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 12 2810G_(ds) ^(m)C_(es)A_(ks)A_(es)T_(ks)A_(e) 1198467 2563 2578 123588 123603TAGAGTATGTGGCAATT_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 27 2811G_(ds)G_(es) ^(m)C_(ks)A_(es)A_(ks)T_(e) 1198468 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 22 963T_(ds)G_(es)G_(ks) ^(m)C_(es)AlcsA_(e) 1198469 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 23 810G_(ds)T_(es)G_(ks)G_(es) ^(m)C_(ks)A_(e) 1198470 2566 2581 123591 123606TATTAGAGTATGTGGCT_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 17 2812T_(ds)G_(es)T_(ks)G_(es)G_(ks) ^(m)C_(e) 1198471 2567 2582 123592 123607ATATTAGAGTATGTGGA_(ks)T_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 21 2813A_(ds)T_(es)G_(ks)T_(es)G_(ks)G_(e) 1198472 2568 2583 123593 123608TATATTAGAGTATGTGT_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 60 2814T_(ds)A_(es)T_(ks)G_(es)T_(ks)G_(e) 1198473 2570 2585 123595 123610TCTATATTAGAGTATGT_(kshu m)C_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 66 887A_(ds)G_(es)T_(ks)A_(es)T_(ks)G_(e) 1198479 4595 4610 125620 125635TTACATTAGGAACAAG T_(ks)T_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 65 2817 G_(ds)A_(ds)A_(es)^(m)C_(ks)A_(es)A_(ks)G_(e) 1198480 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ks)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 75 2818 G_(ds)G_(es)A_(ks)A_(es)^(m)C_(ks)A_(e) 1198481 4598 4613 125623 125638 CTTTTACATTAGGAAC^(m)C_(ks)T_(ks)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) 72 1124T_(ds)A_(ds)G_(es)G_(ks)A_(es)A_(ks) ^(m)C_(e) 1198482 4599 4614 125624125639 ACTTTTACATTAGGAA A_(ks) ^(m)X_(ks)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 63 2819 T_(ds)T_(ds)A_(es)G_(ks)G_(es)A_(ks)A_(e)1198483 4600 4615 125625 125640 CACTTTTACATTAGGA ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 31 1200A_(ds)T_(ds)T_(es)A_(ks)G_(es)G_(ks)A_(e) 1198484 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 18 1276C_(ds)A_(ds)T_(es)T_(ks)A_(es)G_(ks)G_(e) 1198485 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 64 2820 A_(ds)^(m)C_(ds)A_(es)T_(ks)T_(es)A_(ks)G_(e)

TABLE 44Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ ID ID SEQ SEQ NO: 1 NO: 1 ID NO: ID NO: YAP1 SEQ Compound StartStop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5' to 3')CHEMISTRY NOTATION UTC) NO 715487 3630 3645 124655 124670ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds) 18 52 A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 9 810T_(ds)G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554123569 GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds) 7 2800 T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1095603 4443 4458 125468 125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 29 2872A_(ds)T_(ds)A_(ds)A_(es) ^(m)C_(ks)T_(es)G_(ks)G_(e) 1095621 4441 4456125466 125481 TGAGGTATAACTGGGCT_(ks)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 22 1580 A_(ds)^(m)C_(ds)T_(es)G_(ks)G_(es)G_(ks) ^(m)C_(e) 1095622 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 44 2801A_(ds)A_(ds) ^(m)C_(es)T_(ks)G_(es)G_(ks)G_(e) 1095623 4444 4459 125469125484 CACTGAGGTATAACTG ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds) 57 2802T_(ds)A_(ds)T_(ds)A_(es)A_(ks) ^(m)C_(es)T_(ks)G_(e) 1198474 4436 4451125461 125476 TATAACTGGGCAAATT T_(ks)A_(ks)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds) 68 2815 G_(ds)^(m)C_(ds)A_(es)A_(ks)A_(es)T_(ks)T_(e) 1198475 4438 4453 125463 125478GGTATAACTGGGCAAA G_(ks)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds) 25 1427 G_(ds)G_(ds)G_(es) ^(m)C_(ks)A_(es)A_(ks)A_(e)1198476 4439 4454 125464 125479 AGGTATAACTGGGCAAA_(ks)G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 31 905C_(ds)T_(ds)G_(ds)G_(es)G_(ks) ^(m)C_(es)A_(ks)A_(e) 1198477 4440 4455125465 125480 GAGGTATAACTGGGCAG_(ks)A_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 47 1503C_(ds)T_(ds)G_(es)G_(ks)G_(es) ^(m)C_(ks)A_(e) 1198478 4446 4461 125471125486 AACACTGAGGTATAAC A_(ks)A_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds) 60 2816G_(ds)G_(ds)T_(ds)A_(es)T_(ks)A_(es)A_(ks) ^(m)C_(e) 1198486 4603 4618125628 125643 AAGCACTTTTACATTA A_(ks)A_(ks)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds) 39 2821 T_(ds)T_(ds)A_(ds)^(m)C_(es)A_(ks)T_(es)T_(ks)A_(e) 1198487 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds) 62 2822 T_(ds)T_(ds)T_(ds)T_(es)A_(ks) ^(m)C_(es)A_(ks)T_(e)1198488 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 66 2823T_(ds)G_(ds)A_(ds)A_(es)A_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e) 1198489 47974812 125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 50 2824C_(ds)T_(ds)G_(es)A_(ks)A_(es)A_(ks) ^(m)C_(e) 1198490 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 53 2825 T_(ds)^(m)C_(ds)T_(es)G_(ks)A_(es)A_(ks)A_(e) 1198491 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 22 2826A_(ds)T_(ds) ^(m)C_(es)T_(ks)G_(es)A_(ks)A_(e) 1198492 4800 4815 125825125840 GCTTTGGAAGATCTGA G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 15 2044G_(ds)A_(ds)T_(es) ^(m)C_(ks)T_(es)G_(ks)A_(e) 1198493 4801 4816 125826125841 TGCTTTGGAAGATCTG T_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) 28 2121A_(ds)G_(ds)A_(es)T_(ks) ^(m)C_(es)T_(ks)G_(e) 1198494 4802 4817 125827125842 GTGCTTTGGAAGATCT G_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 15 2827A_(ds)A_(ds)G_(es)A_(ks)T_(es) ^(m)C_(ks)T_(e) 1198495 4803 4818 125828125843 AGTGCTTTGGAAGATC A_(ks)G_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds) 22 2828G_(ds)A_(ds)A_(es)G_(ks)A_(es)T_(ks) ^(m)C_(e) 1198496 4805 4820 125830125845 ATAGTGCTTTGGAAGA A_(ks)T_(ks)A_(ds)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds) 46 2891 T_(ds)G_(ds)G_(es)A_(ks)A_(es)G_(ks)A_(e)1198497 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ks)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 22 2830T_(ds)G_(ds)G_(ds)T_(es)T_(ks)T_(es)T_(ks)T_(e) 1198498 N/A N/A 9473194746 TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds) 39 2831 A_(ds)T_(ds)G_(es)G_(ks)T_(es)T_(ks)T_(e) 1198499 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 13 2832C_(ds)A_(ds)T_(es)G_(ks)G_(es)T_(ks)T_(e) 1198500 N/A N/A 94733 94748ATTTAGGATGCATGGT A_(ks)T_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)17 2833 G_(ds) ^(m)C_(ds)A_(es)T_(ks)G_(es)G_(ks)T_(e) 1198501 N/A N/A94734 94749 GATTTAGGATGCATGGG_(ks)A_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 5 2834T_(ds)G_(ds) ^(m)C_(es)A_(ks)T_(es)G_(ks)G_(e) 1198502 N/A N/A 9473594750 AGATTTAGGATGCATGA_(ks)G_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 16 2835A_(ds)T_(ds)G_(es) ^(m)C_(ks)A_(es)T_(ks)G_(e) 1198503 N/A N/A 9473694751 CAGATTTAGGATGCAT^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 31 2836G_(ds)A_(ds)T_(es)G_(ks) ^(m)C_(es)A_(ks)T_(e) 1198504 N/A N/A 9473794752 TCAGATTTAGGATGCA T_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds) 15 2837G_(ds)G_(ds)A_(es)T_(ks)G_(es) ^(m)C_(ks)A_(e) 1198505 N/A N/A 9473994754 ATTCAGATTTAGGATG A_(ks)T_(ks)T_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds) 73 2838T_(ds)A_(ds)G_(es)G_(ks)A_(es)T_(ks)G_(e) 1198506 N/A N/A 115903 115918ATATGGTTTTGTGTGT A_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)47 2839 T_(ds)G_(ds)T_(es)G_(ks)T_(es)G_(ks)T_(e) 1198507 N/A N/A 115905115920 TTATATGGTTTTGTGTT_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 17 2840T_(ds)T_(ds)T_(es)G_(ks)T_(es)G_(ks)T_(e) 1198508 N/A N/A 115906 115921CTTATATGGTTTTGTG^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 22 2788T_(ds)T_(ds)T_(es)T_(ks)G_(es)T_(ks)G_(e) 1198509 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 20 2841G_(ds)T_(ds)T_(es)T_(ks)T_(es)G_(ks)T_(e) 1198510 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 8 2842T_(ds)G_(ds)G_(ds)T_(es)T_(ks)T_(es)T_(ks)G_(e) 1198511 N/A N/A 115909115924 ACTCTTATATGGTTTT A_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 53 2859A_(ds)T_(ds)G_(ds)G_(es)T_(ks)T_(es)T_(ks)T_(e) 1198512 N/A N/A 115910115925 AACTCTTATATGGTTT A_(ks)A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 62 2860T_(ds)A_(ds)T_(ds)G_(es)G_(ks)T_(es)T_(ks)T_(e) 1198513 N/A N/A 115911115926 CAACTCTTATATGGTT ^(m)C_(ks)A_(ks)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds) 63 2861A_(ds)T_(ds)A_(ds)T_(es)G_(ks)G_(es)T_(ks)T_(e) 1198514 N/A N/A 115913115928 GACAACTCTTATATGG G_(ks)A_(ks) ^(m)C_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds) 53 2862T_(ds)T_(ds)A_(ds)T_(es)A_(ks)T_(es)G_(ks)G_(e) 1198515 N/A N/A 117325117340 ATTGCAATCTGTCTGA A_(ks)T_(ks)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m) 44 2843 C_(ds)T_(ds)G_(ds)T_(es)^(m)C_(ks)T_(es)G_(ks)A_(e) 1198516 N/A N/A 117327 117342ATATTGCAATCTGTCT A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds) 50 2844 T_(ds) ^(m)C_(ds)T_(es)G_(ks)T_(es)^(m)C_(ks)T_(e) 1198517 N/A N/A 117328 117343 AATATTGCAATCTGTCA_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 36 2845A_(ds)T_(ds) ^(m)C_(es)T_(ks)G_(es)T_(ks) ^(m)C_(e) 1198518 N/A N/A117329 117344 TAATATTGCAATCTGTT_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 71 2846A_(ds)A_(ds)T_(es) ^(m)C_(ks)T_(es)G_(ks)T_(e) 1198519 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 20 1404C_(ds)A_(ds)A_(es)T_(ks) ^(m)C_(es)T_(ks)G_(e) 1198520 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 51 2847 G_(ds)^(m)C_(ds)A_(es)A_(ks)T_(es) ^(m)C_(ks)T_(e) 1198521 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 44 2848T_(ds)G_(ds) ^(m)C_(es)A_(ks)A_(es)T_(ks) ^(m)C_(e) 1198522 N/A N/A117333 117348 TATGTAATATTGCAATT_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds) 37 2849T_(ds)T_(ds)G_(es) ^(m)C_(ks)A_(es)A_(ks)T_(e) 1198523 N/A N/A 117335117350 TTTATGTAATATTGCAT_(ks)T_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 93 2850T_(ds)A_(ds)T_(es)T_(ks)G_(es) ^(m)C_(ks)A_(e) 1198524 N/A N/A 117755117770 TGTATGTCAGAAGAGT T_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds) 3 2863 G_(ds)A_(ds)A_(es)G_(ks)A_(es)G_(ks)T_(e)1198525 N/A N/A 117757 117772 AGTGTATGTCAGAAGAA_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 2 2864C_(ds)A_(ds)G_(es)A_(ks)A_(es)G_(ks)A_(e) 1198526 N/A N/A 117758 117773AAGTGTATGTCAGAAG A_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)2 2865 T_(ds) ^(m)C_(ds)A_(es)G_(ks)A_(es)A_(ks)G_(e) 1198527 N/A N/A117759 117774 AAAGTGTATGTCAGAAA_(ks)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 5 2866G_(ds)T_(ds) ^(m)C_(es)A_(ks)G_(es)A_(ks)A_(e) 1198528 N/A N/A 117760117775 TAAAGTGTATGTCAGAT_(ks)A_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 14 2867T_(ds)G_(ds)T_(es) ^(m)C_(ks)A_(es)G_(ks)A_(e) 1198529 N/A N/A 117761117776 TTAAAGTGTATGTCAGT_(ks)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 17 2868A_(ds)T_(ds)G_(es)T_(ks) ^(m)C_(es)A_(ks)G_(e) 1198530 N/A N/A 117762117777 TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 29 2869T_(ds)A_(ds)T_(es)G_(ks)T_(es) ^(m)C_(ks)A_(e) 1198531 N/A N/A 117763117778 CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 21 1634G_(ds)T_(ds)A_(es)T_(ks)G_(es)T_(ks) ^(m)C_(e) 1198532 N/A N/A 117765117780 AACTTTAAAGTGTATG A_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) 36 2870G_(ds)T_(ds)G_(es)T_(ks)A_(es)T_(ks)G_(e) 1198533 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(ks)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 35 2851 C_(ds) ^(m)C_(ds)A_(es)G_(ks)A_(es)T_(ks)T_(e)1198534 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 30 2852 T_(ds)^(m)C_(ds) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(ks)A_(e) 1198535 N/A N/A 119670119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 35 2853T_(ds)T_(ds) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(e) 1198536 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds) 20 2854T_(ds)T_(ds)T_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(e) 1198537 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 24 1101G_(ds)G_(ds)T_(ds)T_(es)T_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(e) 1198538N/A N/A 119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 29 2855A_(ds)G_(ds)G_(ds)T_(es)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 1198539 N/AN/A 119674 119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 54 2856A_(ds)A_(ds)G_(ds)G_(es)T_(ks)T_(es)T_(ks) ^(m)C_(e) 1198540 N/A N/A119675 119690 AGACTAAGTAAGGTTT A_(ks)G_(ks)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 51 2857T_(ds)A_(ds)A_(ds)G_(es)G_(ks)T_(es)T_(ks)T_(e) 1198541 N/A N/A 119677119692 TTAGACTAAGTAAGGT T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds) 34 2858G_(ds)T_(ds)A_(es)A_(ks)G_(es)G_(ks)T_(e) 1198890 2524 2539 123549123564 TGTCTCATGCCTTATA T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds) 19 2803 G_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)T_(ds)A_(ks)T_(ds)A_(k) 1198891 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 18 2804 A_(ds)T_(ds)G_(ds) ^(m)C_(ks)^(m)C_(ds)T_(ks)T_(ds)A_(k) 1198892 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m) 24 2805 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ds) ^(m)C_(ks)T_(ds)T_(k)1198899 2560 2575 123585 123600 AGTATGTGGCAATAATA_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m) 75 2809C_(ds)A_(ds)A_(ks)T_(ds)A_(ks)A_(ds)T_(k) 1198900 2562 2577 123587123602 AGAGTATGTGGCAATAA_(ks)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 11 2810G_(ds)G_(ds) ^(m)C_(ks)A_(ds)A_(ks)T_(ds)A_(k) 1198901 2563 2578 123588123603 TAGAGTATGTGGCAATT_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 28 2811T_(ds)G_(ds)G_(ks) ^(m)C_(ds)A_(ks)A_(ds)T_(k) 1198902 2564 2579 123589123604 TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 13 963G_(ds)T_(ds)G_(ks)G_(ds) ^(m)C_(ks)A_(ds)A_(k) 1198903 2565 2580 123590123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 24 810T_(ds)G_(ds)T_(ks)G_(ds)G_(ks) ^(m)C_(ds)A_(k) 1198904 2566 2581 123591123606 TATTAGAGTATGTGGCT_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 12 2812A_(ds)T_(ds)G_(ks)T_(ds)G_(ks)G_(ds) ^(m)C_(k) 1198905 2567 2582 123592123607 ATATTAGAGTATGTGGA_(ks)T_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 5 2813T_(ds)A_(ds)T_(ks)G_(ds)T_(ks)G_(ds)G_(k) 1198906 2568 2583 123593123608 TATATTAGAGTATGTGT_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds) 56 2814G_(ds)T_(ds)A_(ks)T_(ds)G_(ks)T_(ds)G_(k) 1198907 2570 2585 123595123610 TCTATATTAGAGTATG T_(ks)^(m)C_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 74 887G_(ds)A_(ds)G_(ks)T_(ds)A_(ks)T_(ds)G_(k)

TABLE 45Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ ID ID SEQ SEQ NO: 1 NO: 1 ID NO: ID NO: YAP1 SEQ Compound StartStop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5' to 3')CHEMISTRY NOTATION UTC) NO 715487 3630 3645 124655 124670ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 28 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 15 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds) 9 2800 T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1095491 4443 4458 125468 125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds) 65 392T_(ds)A_(ds)A_(ks) ^(m)C_(ds)T_(ks)G_(ds)G_(k) 1095509 4441 4456 125466125481 TGAGGTATAACTGGGCT_(ks)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 291580 C_(ds)T_(ks)G_(ds)G_(ks)G_(ds) ^(m)C_(k) 1095510 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 35 2801A_(ds)A_(ds) ^(m)C_(ks)T_(ds)G_(ks)G_(ds)G_(k) 1095511 4444 4459 125469125484 CACTGAGGTATAACTG ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 46 2802A_(ds)T_(ds)A_(ks)A_(ds) ^(m)C_(ks)T_(ds)G_(k) 1198893 2528 2543 123553123568 AAATTGTCTCATGCCT A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 58 443 C_(ds)A_(ds)T_(ks)G_(ds) ^(m)C_(ks)^(m)C_(ds)T_(k) 1198894 2529 2544 123554 123569 GAAATTGTCTCATGCCG_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 57 2800T_(ds) ^(m)C_(ds)A_(ks)T_(ds)G_(ks) ^(m)C_(ds) ^(m)C_(k) 1198895 25302545 123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 22 2806C_(ds)T_(ds) ^(m)C_(ks)A_(ds)T_(ks)G_(ds) ^(m)C_(k) 1198896 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 592807 C_(ds)T_(ks) ^(m)C_(ds)A_(ks)T_(ds)G_(k) 1198897 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 61 2808T_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(ks)A_(ds)T_(k) 1198898 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 53 656T_(ds)G_(ks)T_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(k) 1198908 4436 4451 125461125476 TATAACTGGGCAAATT T_(ks)A_(ks)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds) 124 2815 G_(ds)^(m)C_(ds)A_(ks)A_(ds)A_(ks)T_(ds)T_(k) 1198909 4438 4453 125463 125478GGTATAACTGGGCAAA G_(ks)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds) 56 1427 G_(ds)G_(ds)G_(ks) ^(m)C_(ds)A_(ks)A_(ds)A_(k)1198910 4439 4454 125464 125479 AGGTATAACTGGGCAAA_(ks)G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) 40 905T_(ds)G_(ds)G_(ks)G_(ds) ^(m)C_(ks)A_(ds)A_(k) 1198911 4440 4455 125465125480 GAGGTATAACTGGGCAG_(ks)A_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 26 1503C_(ds)T_(ds)G_(ks)G_(ds)G_(ks) ^(m)C_(ds)A_(k) 1198912 4446 4461 125471125486 AACACTGAGGTATAAC A_(ks)A_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 78 2816G_(ds)T_(ds)A_(ks)T_(ds)A_(ks)A_(ds) ^(m)C_(k) 1198913 4595 4610 125620125635 TTACATTAGGAACAAG T_(ks)T_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 86 2817 G_(ds)A_(ds)A_(ks)^(m)C_(ds)A_(ks)A_(ds)G_(k) 1198914 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ks)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 68 2818 G_(ds)G_(ks)A_(ds)A_(ks)^(m)C_(ds)A_(k) 1198915 4598 4613 125623 125638 CTTTTACATTAGGAAC^(m)C_(ks)T_(ks)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) 37 1124T_(ds)A_(ds)G_(ks)G_(ds)A_(ks)A_(ds) ^(m)C_(k) 1198916 4599 4614 125624125639 ACTTTTACATTAGGAA A_(ks) ^(m)C_(ks)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 59 2819 T_(ds)T_(ds)A_(ks)G_(ds)G_(ks)A_(ds)A_(k)1198917 4600 4615 125625 125640 CACTTTTACATTAGGA ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 21 1200A_(ds)T_(ds)T_(ks)A_(ds)G_(ks)G_(ds)A_(k) 1198918 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 27 1276^(m)C_(ds)A_(ds)T_(ks)T_(ds)A_(ks)G_(ds)G_(k) 1198919 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 60 2820 A_(ds)^(m)C_(ds)A_(ks)T_(ds)T_(ks)A_(ds)G_(k) 1198920 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(ks)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 54 2821 T_(ds)A_(ds)^(m)C_(ks)A_(ds)T_(ks)T_(ds)A_(k) 1198921 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 89 2822 T_(ds)T_(ds)T_(ks)A_(ds) ^(m)C_(ks)A_(ds)T_(k)1198922 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 59 2823G_(ds)A_(ds)A_(ks)A_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(k) 1198923 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 73 2824C_(ds)T_(ds)G_(ks)A_(ds)A_(ks)A_(ds) ^(m)C_(k) 1198924 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 752825 C_(ds)T_(ks)G_(ds)A_(ks)A_(ds)A_(k) 1198925 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 52 2826A_(ds)T_(ds) ^(m)C_(ks)T_(ds)G_(ks)A_(ds)A_(k) 1198926 4800 4815 125825125840 GCTTTGGAAGATCTGA G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 45 2044G_(ds)A_(ds)T_(ks) ^(m)C_(ds)T_(ks)G_(ds)A_(k) 1198927 4801 4816 125826125841 TGCTTTGGAAGATCTG T_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) 50 2121A_(ds)G_(ds)A_(ks)T_(ds) ^(m)C_(ks)T_(ds)G_(k) 1198928 4802 4817 125827125842 GTGCTTTGGAAGATCT G_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 28 2827A_(ds)A_(ds)G_(ks)A_(ds)T_(ks) ^(m)C_(ds)T_(k) 1198929 4803 4818 125828125843 AGTGCTTTGGAAGATC A_(ks)G_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds) 43 2828G_(ds)G_(ds)A_(ks)G_(ds)A_(ks)T_(ds) ^(m)C_(k) 1198930 4805 4820 125830125845 ATAGTGCTTTGGAAGA A_(ks)T_(ks)A_(ds)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 68 2829 G_(ds)G_(ks)A_(ds)A_(ks)G_(ds)A_(k)1198931 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ks)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) 47 2830G_(ds)G_(ds)T_(ks)T_(ds)T_(ks)T_(ds)T_(k) 1198932 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds) 35 2831 A_(ds)T_(ds)G_(ks)G_(ds)T_(ks)T_(ds)T_(k) 1198933 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 69 2832C_(ds)A_(ds)T_(ks)G_(ds)G_(ks)T_(ds)T_(k) 1198934 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 562833 C_(ds)A_(ks)T_(ds)G_(ks)G_(ds)T_(k) 1198935 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 18 2834G_(ds) ^(m)C_(ks)A_(ds)T_(ks)G_(ds)G_(k) 1198936 N/A N/A 94735 94750AGATTTAGGATGCATGA_(ks)G_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 38 2835T_(ds)G_(ks) ^(m)C_(ds)A_(ks)T_(ds)G_(k) 1198937 N/A N/A 94736 94751CAGATTTAGGATGCAT^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 48 2836G_(ds)A_(ds)T_(ks)G_(ds) ^(m)C_(ks)A_(ds)T_(k) 1198938 N/A N/A 9473794752 TCAGATTTAGGATGCA T_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds) 59 2837G_(ds)G_(ds)A_(ks)T_(ds)G_(ks) ^(m)C_(ds)A_(k) 1198939 N/A N/A 9473994754 ATTCAGATTTAGGATG A_(ks)T_(ks)T_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds) 102 28388A_(ds)G_(ks)G_(ds)A_(ks)T_(ds)G_(k) 1198940 N/A N/A 115903 115918ATATGGTTTTGTGTGTA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 51 2881G_(ds)T_(ks)G_(ds)T_(ks)G_(ds)T_(k) 1198941 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 35 2840T_(ds)T_(ks)G_(ds)T_(ks)G_(ds)T_(k) 1198942 N/A N/A 115906 115921CTTATATGGTTTTGTG^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 42 2788T_(ds)T_(ks)T_(ds)G_(ks)T_(ds)G_(k) 1198943 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 31 2841T_(ds)T_(ks)T_(ds)T_(ks)G_(ds)T_(k) 1198944 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 34 2842G_(ds)G_(ds)T_(ks)T_(ds)T_(ks)T_(ds)G_(k) 1198945 N/A N/A 115909 115924ACTCTTATATGGTTTT A_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 48 2859T_(ds)G_(ds)G_(ks)T_(ds)T_(ks)T_(ds)T_(k) 1198946 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 72 2860A_(ds)T_(ds)G_(ks)G_(ds)T_(ks)T_(ds)T_(k) 1198947 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(ks)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 88 2861T_(ds)A_(ds)T_(ks)G_(ds)G_(ks)T_(ds)T_(k) 1198948 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(ks) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds) 96 2862 T_(ds)A_(ds)T_(ks)A_(ds)T_(ks)G_(ds)G_(k)1198949 N/A N/A 117325 117340 ATTGCAATCTGTCTGA A_(ks)T_(ks)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) 61 2843 T_(ds)G_(ds)T_(ks)^(m)C_(ds)T_(ks)G_(ds)A_(k) 1198950 N/A N/A 117327 117342ATATTGCAATCTGTCT A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds) 85 2844 T_(ds) ^(m)C_(ds)T_(ks)G_(ds)T_(ks)^(m)C_(ds)T_(k) 1198951 N/A N/A 117328 117343 AATATTGCAATCTGTCA_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 81 2845A_(ds)T_(ds) ^(m)C_(ks)T_(ds)G_(ks)T_(ds) ^(m)C_(k) 1198952 N/A N/A117329 117344 TAATATTGCAATCTGTT_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 77 2846A_(ds)A_(ks)T_(ks) ^(m)C_(ds)T_(ks)G_(ds)T_(k) 1198953 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 58 1404C_(ds)A_(ds)A_(ks)T_(ds) ^(m)C_(ks)T_(ds)G_(k) 1198954 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 942847 C_(ds)A_(ks)A_(ds)T_(ks) ^(m)C_(ds)T_(k) 1198955 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 92 2848G_(ds) ^(m)C_(ks)A_(ds)A_(ks)T_(ds) ^(m)C_(k) 1198956 N/A N/A 117333117348 TATGTAATATTGCAATT_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 76 2849T_(ds)G_(ks) ^(m)C_(ds)A_(ks)A_(ds)T_(k) 1198957 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 81 2850A_(ds)T_(ks)T_(ds)G_(ks) ^(m)C_(ds)A_(k) 1198958 N/A N/A 117755 117770TGTATGTCAGAAGAGT T_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds) 12 2863 G_(ds)A_(ds)A_(ks)G_(ds)A_(ks)G_(ds)T_(k)1198959 N/A N/A 117757 117772 AGTGTATGTCAGAAGAA_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 8 2864C_(ds)A_(ds)G_(ks)A_(ds)A_(ks)G_(ds)A_(k) 1198960 N/A N/A 117758 117773AAGTGTATGTCAGAAGA_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 6 2865C_(ds)A_(ks)G_(ds)A_(ks)A_(ds)G_(k) 1198961 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 12 2866T_(ds) ^(m)C_(ks)A_(ds)G_(ks)A_(ds)A_(k) 1198962 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 52 2867G_(ds)T_(ks) ^(m)C_(ds)A_(ks)G_(ds)A_(k) 1198963 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 27 2868T_(ds)G_(ks)T_(ds) ^(m)C_(ks)A_(ds)G_(k) 1198964 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 59 2869A_(ds)T_(ks)G_(ds)T_(ks) ^(m)C_(ds)A_(k) 1198965 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 95 1634G_(ds)T_(ds)A_(ks)T_(ds)G_(ks)T_(ds) ^(m)C_(k) 1198967 N/A N/A 119667119682 TAAGGTTTCCCAGATT T_(ks)A_(ks)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 65 2851 C_(ds) ^(m)C_(ds)A_(ks)G_(ds)A_(ks)T_(ds)T_(k)1198968 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 572852 C_(ds) ^(m)C_(ks) ^(m)C_(ds)A_(ks)G_(ds)A_(k) 1198969 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 31 2853T_(ds) ^(m)C_(ks) ^(m)C_(ds) ^(m)C_(ks)A_(ds)G_(k) 1198970 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 29 2854T_(ds)T_(ks) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ds)A_(k) 1198971 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 31 1101G_(ds)T_(ds)T_(ks)T_(ds) ^(m)C_(ks) ^(m)C_(ds) ^(m)C_(k) 1198972 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 46 2855G_(ds)G_(ds)T_(ks)T_(ds)T_(ks) ^(m)C_(ds) ^(m)C_(k) 1198973 N/A N/A119674 119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 53 2856A_(ds)G_(ds)G_(ks)T_(ds)T_(ks)T_(ds) ^(m)C_(k) 1198974 N/A N/A 119675119690 AGACTAAGTAAGGTTT A_(ks)G_(ks)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 73 2857A_(ds)A_(ds)G_(ks)G_(ds)T_(ks)T_(ds)T_(k) 1198975 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds) 52 2858G_(ds)T_(ds)A_(ks)A_(ds)G_(ks)G_(ds)T_(k)

Table 46Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ    ID ID SEQ ID SEQ ID YAP1 NO: 1 NO: 1 NO: 2 NO: 2 SEQ SEQCompound Start Stop Start Stop Sequence YAP1 ID Number Site Site SiteSite (5' to 3') CHEMSITRY NOTATION (% UT) NO 715487 3630 3645 124655124670 ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds) 25 52 A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 16 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 14 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1095407 4443 4458 125468 125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 54 392A_(ds)A_(ks) ^(m)C_(es)T_(ks)G_(es)G_(k) 1095425 4441 4456 125466 125481TGAGGTATAACTGGGCT_(ks)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 571580 C_(ds)T_(ks)G_(es)G_(ks)G_(es) ^(m)C_(k) 1095426 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 54 2801A_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(es)G_(k) 1095427 4444 4459 125469 125484CACTGAGGTATAACTG ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 45 2802A_(ds)T_(ds)A_(ks)A_(es) ^(m)C_(ks)T_(es)G_(k) 1198804 2524 2539 123549123564 TGTCTCATGCCTTATA T_(ks)G_(ks)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m) 22 2803 C_(ds)^(m)C_(ds)T_(ks)T_(es)A_(ks)T_(es)A_(k) 1198805 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds) 23 2804 G_(ds) ^(m)C_(ks)^(m)C_(es)T_(ks)T_(es)A_(k) 1198806 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 33 2805 A_(ds)T_(ds)G_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es)T_(k)1198807 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 44 433C_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks) ^(m)C_(es)T_(k) 1198808 2529 2544123554 123569 GAAATTGTCTCATGCCG_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)40 2800 C_(ds)A_(ks)T_(es)G_(ks) ^(m)C_(es) ^(m)C_(k) 1198809 2530 2545123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 272806 T_(ds) ^(m)C_(ks)A_(es)T_(ks)G_(es) ^(m)C_(k) 1198810 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 502807 C_(ds)T_(ks) ^(m)C_(es)A_(ks)T_(es)G_(k) 1198811 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 38 2808T_(ds) ^(m)C_(ks)T_(es) ^(m)C_(ks)A_(es)T_(k) 1198812 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 26 656T_(ds)G_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 1198813 2560 2575 123585123600 AGTATGTGGCAATAATA_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) 552809 A_(ds)A_(ks)T_(es)A_(ks)A_(es)T_(k) 1198814 2562 2577 123587 123602AGAGTATGTGGCAATAA_(ks)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 13 2810G_(ds) ^(m)C_(ks)A_(es)A_(ks)T_(es)A_(K) 1198815 2563 2578 123588 123603TAGAGTATGTGGCAATT_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 24 2811G_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(es)T_(k) 1198816 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 27 963T_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(es)A_(k) 1198817 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)43 810G_(ds)T_(ks)G_(es)G_(ks) ^(m)C_(es)A_(k) 1198818 2566 2581 123591 123606TATTAGAGTATGTGGC T_(ks)A_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)15 2812 T_(ds)G_(ks)T_(es)G_(ks)G_(es) ^(m)C_(k) 1198819 2567 2582123592 123607 ATATTAGAGTATGTGGA_(ks)T_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 44 2813A_(ds)T_(ks)G_(es)T_(ks)G_(es)G_(k) 1198820 2568 2583 123593 123608TATATTAGAGTATGTGT_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 62 2814T_(ds)A_(ks)T_(es)G_(ks)T_(es)G_(k) 1198821 2570 2585 123595 123610TCTATATTAGAGTATG T_(ks)^(m)C_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 62 887A_(ds)G_(ks)T_(es)A_(ks)T_(es)G_(k) 1198822 4436 4451 125461 125476TATAACTGGGCAAATT T_(ks)A_(ks)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m) 97 2815C_(ds)A_(ks)A_(es)A_(ks)T_(es)T_(k) 1198823 4438 4453 125463 125478GGTATAACTGGGCAAA G_(ks)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds) 65 1427 G_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(es)A_(k)1198824 4439 4454 125464 125479 AGGTATAACTGGGCAAA_(ks)G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) 72 905G_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(es)A_(k) 1198825 4440 4455 125465 125480GAGGTATAACTGGGCA G_(ks)A_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds) 64 1503 T_(ds)G_(ks)G_(es)G_(ks) ^(m)C_(es)A_(k) 1198826 44464461 125471 125486 AACACTGAGGTATAAC A_(ks)A_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 64 2816G_(ds)T_(ds)A_(ks)T_(es)A_(ks)A_(es) ^(m)C_(k) 1198827 4595 4610 125620125635 TTACATTAGGAACAAG T_(ks)T_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 60 2817 A_(ds)A_(ks)^(m)C_(es)A_(ks)A_(es)G_(k) 1198828 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ks)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 59 2818 G_(ds)G_(ks)A_(es)A_(ks)^(m)C_(es)A_(k) 1198829 4598 4613 125623 125638 CTTTTACATTAGGAAC^(m)C_(ks)T_(ks)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) 36 1124A_(ds)G_(ks)G_(es)A_(ks)A_(es) ^(m)C_(k) 1198830 4599 4614 125624 125639ACTTTTACATTAGGAA ^(m)A_(ks)C_(ks)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds) 37 2819 T_(ds)A_(ks)G_(es)G_(ks)A_(es)A_(k)1198831 4600 4615 125625 125640 CACTTTTACATTAGGA ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 12 1200A_(ds)T_(ds)T_(ks)A_(es)G_(ks)G_(es)A_(k) 1198832 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 20 1276C_(ds)A_(ds)T_(ks)T_(es)A_(ks)G_(es)G_(k) 1198833 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 54 2820 A_(ds)^(m)C_(ds)A_(ks)T_(es)T_(ks)A_(es)G_(k) 1198834 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(ks)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 54 2821 T_(ds)A_(ds)^(m)C_(ks)A_(es)T_(ks)T_(es)A_(k) 1198835 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 85 2822 T_(ds)T_(ds)T_(ks)A_(es) ^(m)C_(ks)A_(es)T_(k)1198836 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) 432823 A_(ds)A_(ks)A_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 1198837 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 662824 T_(ds)G_(ks)A_(es)A_(ks)A_(es) ^(m)C_(k) 1198838 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 662825 C_(ds)T_(ks)G_(es)A_(ks)A_(es)A_(k) 1198839 4799 4814 125824 125839CTTTGGAAGATCTGAAmC_(ks)T_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 36 2826T_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(es)A_(k) 1198840 4800 4815 125825 125840GCTTTGGAAGATCTGA G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 26 2044A_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(es)A_(k) 1198841 4801 4816 125826 125841TGCTTTGGAAGATCTG T_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 116 2121G_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(es)G_(k) 1198842 4802 4817 125827 125842GTGCTTTGGAAGATCT G_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) 37 2827A_(ds)G_(ks)A_(es)T_(ks) ^(m)C_(es)T_(k) 1198843 4803 4818 125828 125843AGTGCTTTGGAAGATC A_(ks)G_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 45 2828A_(ds)A_(ks)G_(es)A_(ks)T_(es) ^(m)C_(k) 1198844 4805 4820 125830 125845ATAGTGCTTTGGAAGA A_(ks)T_(ks)A_(ds)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 56 2829 G_(ds)G_(ks)A_(es)A_(ks)G_(es)A_(k)1198845 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ks)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds) 432830 G_(ds)T_(ks)T_(es)T_(ks)T_(es)T_(k) 1198846 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 34 2831 T_(ds)G_(ks)G_(es)T_(ks)T_(es)T_(k) 1198847 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 512832 A_(ds)T_(ks)G_(es)G_(ks)T_(es)T_(k) 1198848 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 472833 C_(ds)A_(ks)T_(es)G_(ks)G_(es)T_(k) 1198849 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 42 2834G_(ds) ^(m)C_(ks)A_(es)T_(ks)G_(es)G_(k) 1198850 N/A N/A 94735 94750AGATTTAGGATGCATGA_(ks)G_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 33 2835T_(ds)G_(ks) ^(m)C_(es)A_(ks)T_(es)G_(k) 1198851 N/A N/A 94736 94751CAGATTTAGGATGCAT^(m)C_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 82 2836A_(ds)T_(ks)G_(es) ^(m)C_(ks)A_(es)T_(k) 1198852 N/A N/A 94737 94752TCAGATTTAGGATGCA T_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 41 2837G_(ds)A_(ks)T_(es)G_(ks) ^(m)C_(es)A_(k) 1198853 N/A N/A 94739 94754ATTCAGATTTAGGATG A_(ks)T_(ks)T_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds) 105 2838A_(ds)G_(ks)G_(es)A_(ks)T_(es)G_(k) 1198854 N/A N/A 115903 115918ATATGGTTTTGTGTGTA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 56 2839G_(ds)T_(ks)G_(es)T_(ks)G_(es)T_(k) 1198855 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 30 2840T_(ds)T_(ks)G_(es)T_(ks)G_(es)T_(k) 1198856 N/A N/A 115906 115921CTTATATGGTTTTGTGmC_(ks)T_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 20 2788T_(ds)T_(ks)T_(es)G_(ks)T_(es)G_(k) 1198857 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks) ^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)19 2841 T_(ds)T_(ks)T_(es)T_(ks)G_(es)T_(k) 1198863 N/A N/A 117325117340 ATTGCAATCTGTCTGA A_(ks)T_(ks)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) 65 2843 T_(ds)G_(ds)T_(ks)^(m)C_(es)T_(ks)G_(es)A_(k) 1198864 N/A N/A 117327 117342ATATTGCAATCTGTCT A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m) 56 2844 C_(ds)T_(ks)G_(es)T_(ks)^(m)C_(es)T_(k) 1198865 N/A N/A 117328 117343 AATATTGCAATCTGTCA_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) 382845 T_(ds) ^(m)C_(ks)T_(es)G_(ks)T_(es) ^(m)C_(k) 1198866 N/A N/A117329 117344 TAATATTGCAATCTGTT_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 602846 A_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(es)T_(k) 1198867 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 251404 A_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(es)G_(k) 1198868 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 492847 C_(ds)A_(ks)A_(es)T_(ks) ^(m)C_(es)T_(k) 1198869 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 49 2848G_(ds) ^(m)C_(ks)A_(es)A_(ks)T_(es) ^(m)C_(k) 1198870 N/A N/A 117333117348 TATGTAATATTGCAATT_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 86 2849T_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(es)T_(k) 1198871 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 77 2850A_(ds)T_(ks)T_(es)G_(ks) ^(m)C_(es)A_(k) 1198881 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(ks)A_(ds)G_(ds)G_(ds)TdsT_(ds)T_(ds)^(m)C_(ds) ^(m) 36 2851 C_(ds) ^(m)C_(ds)A_(ks)G_(es)A_(ks)T_(es)T_(k)1198882 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 562852 C_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)A_(k) 1198883 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 47 2853T_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(k) 1198884 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 28 2854T_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 1198885 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds) 41 1101T_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(k) 1198886 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 45 2855G_(ds)T_(ks)T_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 1198887 N/A N/A 119674119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 71 2856G_(ds)G_(ks)T_(es)T_(ks)T_(es) ^(m)C_(k) 1198888 N/A N/A 119675 119690AGACTAAGTAAGGTTT A_(ks)G_(ks)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 51 2857A_(ds)G_(ks)G_(es)T_(ks)T_(es)T_(k) 1198889 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 27 2858T_(ds)A_(ks)A_(es)G_(ks)G_(es)T_(k) 1198966 N/A N/A 117765 117780AACTTTAAAGTGTATG A_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) 78 2870T_(ds)G_(ks)T_(ds)A_(ks)T_(ds)G_(k)

Table 47Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ    ID ID SEQ ID SEQ ID YAP1 NO: 1 NO: 1 NO: 2 NO: 2 SEQ SEQCompound Start Stop Start Stop YAP1 ID Number Site Site Site SiteSequence (5' to 3') CHEMSITRY NOTATION (% UT) NO 715487 3630 3645 124655124670 ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 39 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)716444 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(ks)A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 46 443C_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 958497 2534 2549123559 123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 20 656T_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 958499 2565 2580 123590123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(s)T_(ds)A_(ds)T_(ds) 17 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 958499 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 10 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 958500 2570 2585 123595 123610TCTATATTAGAGTATG T_(ks)^(m)C_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 53 887A_(ds)G_(ds)T_(ds)A_(ks)T_(ks)G_(k) 1009324 2560 2575 36419 36434AGTATGTGGCAATAAT A_(ks)G_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds)^(m)C_(ds) 27 2809 63341 63356 A_(ds)A_(ds)T_(ds)A_(ks)A_(ks)T_(k)123585 123600 1009325 2562 2577 63343 63358 AGAGTATGTGGCAATAA_(ks)G_(ks)A_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 16 281071690 71705 G_(ds) ^(m)C_(ds)A_(ds)A_(ks)T_(ks)A_(k) 123587 1236021009326 2566 2581 123591 123606 TATTAGAGTATGTGGCT_(ks)A_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 10 2812T_(ds)G_(ds)T_(ds)G_(ks)G_(ks) ^(m)C_(k) 1009327 2567 2582 123592 123607ATATTAGAGTATGTGGA_(ks)T_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 27 2813A_(ds)T_(ds)G_(ds)T_(ks)G_(ks)G_(k) 1009328 2568 2583 123593 123608TATATTAGAGTATGTGT_(ks)A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 67 2814T_(ds)A_(ds)T_(ds)G_(ks)T_(ks)G_(k) 1009394 2223 2238 123248 123263TATAACTGGGCAAATT T_(ks)A_(ks)T_(ks)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m) 73 2815 4436 4451 125461 125476C_(ds)A_(ds)A_(ds)A_(ks)T_(ks)T_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 5 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1074462 2530 2545 123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 7 2806T_(ds) ^(m)C_(ds)A_(ds)T_(ks)G_(ks) ^(m)C_(k) 1074463 2563 2578 123588123603 TAGAGTATGTGGCAATT_(ks)A_(ks)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 20 2811G_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(k) 1074464 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 5 963T_(ds)G_(s)G_(ds) ^(m)C_(ks)A_(ks)A_(k) 1074754 4598 4613 125623 125638CTTTTACATTAGGAAC ^(m)C_(ks)T_(ks)T_(ks)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds) 69 1124 A_(ds)G_(ds)G_(ds)A_(ks)A_(ks)^(m)C_(k) 1074755 4600 4615 125625 125640 CACTTTTACATTAGGA^(m)C_(ks)A_(ks) ^(m)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 23 1200A_(ds)T_(ds)T_(ds)A_(ds)G_(ks)G_(ks)A_(k) 1074756 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks) ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 8 1276C_(ds)A_(ds)T_(ds)T_(ds)A_(ks)G_(ks)G_(k) 1074798 4800 4815 125825125840 GCTTTGGAAGATCTGA G_(ks)^(m)C_(ks)T_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 19 2044A_(ds)T_(ds) ^(m)C_(ds)T_(ks)G_(ks)A_(k) 1074799 4801 4816 125826 125841TGCTTTGGAAGATCTG T_(ks)G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 21 2121G_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(k) 1076186 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ks)T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 312833 C_(ds)A_(ds)T_(ds)G_(ks)G_(ks)T_(k) 1076187 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(ks)T_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 17 2834G_(ds) ^(m)C_(ds)A_(ds)T_(ks)G_(ks)G_(k) 1076453 N/A N/A 117330 117345GTAATATTGCAATCTG G_(ks)T_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds) 7 1404 A_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(k) 1076481 N/AN/A 119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)13 1101T_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(k) 1096369 4802 4817125827 125842 GTGCTTTGGAAGATCT G_(ks)T_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) 45 2827A_(ds)G_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(k) 1097037 N/A N/A 94735 94750AGATTTAGGATGCATGA_(ks)G_(ks)A_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 38 2835T_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(k) 1097238 N/A N/A 117325 117340ATTGCAATCTGTCTGA A_(ks)T_(ks)T_(ks)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 77 2843 T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks)G_(ks)A_(k)1197176 2524 2539 123549 123564 TGTCTCATGCCTTATA T_(ks)G_(ks)T_(ks)^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m) 17 2803 C_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ks)T_(ks)A_(k) 1197177 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds) 15 2804 T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)T_(ks)A_(k) 1197178 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ks)T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 12 2805 A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)T_(k)1197179 2531 2546 123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 162807 C_(ds)T_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(k) 1197180 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 47 2808T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)A_(ks)T_(k) 1197181 4595 4610 125620125635 TTACATTAGGAACAAG T_(ks)T_(ks)A_(ks)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 87 2817 A_(ds)A_(ds)^(m)C_(ds)A_(ks)A_(ks)G_(k) 1197182 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ks)T_(ks)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 115 2818 G_(ds)G_(ds)A_(ds)A_(ks)^(m)C_(ks)A_(k) 1197183 4599 4614 125624 125639 ACTTTTACATTAGGAA A_(ks)^(m)C_(ks)T_(ks)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds) 41 2819T_(ds)T_(ds)A_(ds)G_(ds)G_(ks)A_(ks)A_(k) 1197184 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 20 2820 A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ks)A_(ks)G_(k) 1197185 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(ks)G_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 55 2821 T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ks)T_(ks)A_(k) 1197186 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ks)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 65 2822 T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ks)T_(k)1197187 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ks)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) 242823 A_(ds)A_(ds)A_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 1197188 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 962824 T_(ds)G_(ds)A_(ds)A_(ks)A_(ks) ^(m)C_(k) 1197189 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 712825 C_(ds)T_(ds)G_(ds)A_(ks)A_(ks)A_(k) 1197190 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ks+lTks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 57 2826T_(ds) ^(m)C_(ds)T_(ds)G_(ks)A_(ks)A_(k) 1197191 4803 4818 125828 125843AGTGCTTTGGAAGATC A_(ks)G_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 40 2828A_(ds)A_(ds)G_(ds)A_(ks)T_(ks) ^(m)C_(k) 1197192 4805 4820 125830 125845ATAGTGCTTTGGAAGA A_(ks)T_(ks)A_(ks)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 39 2829 G_(ds)G_(ds)A_(ds)A_(ks)G_(ks)A_(k)1197193 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ks)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds) 15 2830G_(ds)T_(ds)T_(ds)T_(ks)T_(ks)T_(k) 1197194 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ks)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 37 2831 T_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1197195 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 382832 A_(ds)T_(ds)G_(ds)G_(ks)T_(ks)T_(k) 1197196 N/A N/A 94736 94751CAGATTTAGGATGCAT^(m)C_(ks)A_(ks)G_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)C_(ds) 27 2836A_(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(ks)T_(k) 1197197 N/A N/A 94737 94752TCAGATTTAGGATGCA T_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 20 2837G_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(k) 1197198 N/A N/A 94739 94754ATTCAGATTTAGGATG A_(ks)T_(ks)T_(ks)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds+l) 139 2838A_(ds)G_(ds)G_(ds)A_(ks)T_(ks)G_(k) 1197206 N/A N/A 117327 117342ATATTGCAATCTGTCT A_(ks)T_(ks)A_(ks)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m) 63 2844 C_(ds)T_(ds)G_(ds)T_(ks)^(m)C_(ks)T_(k) 1197207 N/A N/A 117328 117343 AATATTGCAATCTGTCA_(ks)A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) 512845 T_(ds) ^(m)C_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 1197208 N/A N/A117329 117344 TAATATTGCAATCTGTT_(ks)A_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 662846 A_(ds)T_(ds) ^(m)C_(ds)T_(ks)G_(ks)T_(k) 1197209 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 332847 C_(ds)A_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(k) 1197210 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 105 2848G_(ds) ^(m)C_(ds)A_(ds)A_(ks)T_(ks) ^(m)C_(k) 1197211 N/A N/A 117333117348 TATGTAATATTGCAATT_(ks)A_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 80 2849T_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(k) 1197212 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 55 2850A_(ds)T_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(k) 1197220 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(ks)A_(ks)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 32 2851 C_(ds) ^(m)C_(ds)A_(ds)G_(ds)A_(ks)T_(ks)T_(k)1197221 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ks)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 422852 C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(k) 1197222 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 40 2853T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(k) 1197223 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 11 2854T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 1197224 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 24 2855G_(ds)T_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 1197225 N/A N/A 119674119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 46 2856G_(ds)G_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(k) 1197226 N/A N/A 119675 119690AGACTAAGTAAGGTTT A_(ks)G_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 67 2857A_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1197227 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(ks)A_(ks)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 64 2858T_(ds)A_(ds)A_(ds)G_(ks)G_(ks)T_(k) 1198858 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 29 2842G_(ds)G_(ds)T_(ks)T_(es)T_(ks)T_(es)G_(k) 1198859 N/A N/A 115909 115924ACTCTTATATGGTTTT A_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 33 2859T_(ds)G_(ds)G_(ks)T_(es)T_(ks)T_(es)T_(k) 1198860 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 82 2860A_(ds)T_(ds)G_(ks)G_(es)T_(ks)T_(es)T_(k) 1198861 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 100 2861T_(ds)A_(ds)T_(ks)G_(es)G_(ks)T_(es)T_(k) 1198862 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(ks) ^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds) 72 2862 T_(ds)A_(ds)T_(ks)A_(es)T_(ks)G_(es)G_(k)1198872 N/A N/A 117755 117770 TGTATGTCAGAAGAGTT_(ks)G_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds) 8 2863A_(ds)A_(ks)G_(es)A_(ks)G_(es)T_(k) 1198873 N/A N/A 117757 117772AGTGTATGTCAGAAGA A_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds) 4 2864 A_(ds)G_(ks)A_(es)A_(ks)G_(es)A_(k) 1198874 N/A N/A117758 117773 AAGTGTATGTCAGAAGA_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(da)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 2 2865C_(ds)A_(ks)G_(es)A_(ks)A_(es)G_(k) 1198875 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 5 2866T_(ds) ^(m)C_(ks)A_(es)G_(ks)A_(es)A_(k) 1198876 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 31 2867G_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(es)A_(k) 1198877 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 11 2868T_(ds)G_(ks)T_(es) ^(m)C_(ks)A_(es)G_(k) 1198878 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 42 2869A_(ds)T_(ks)G_(es)T_(ks) ^(m)C_(es)A_(k) 1198879 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 29 1634T_(ds)A_(ks)T_(es)G_(ks)T_(es) ^(m)C_(k) 1198880 N/A N/A 117765 117780AACTTTAAAGTGTATG A_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) 98 2870T_(ds)G_(ks)T_(es)A_(ks)T_(es)G_(k)

Table 48Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ    ID ID SEQ ID SEQ ID YAP1 NO: 1 NO: 1 NO: 2 NO: 2 SEQ SEQCompound Start Stop Start Stop YAP1 ID Number Site Site Site SiteSequence (5' to 3') CHEMSITRY NOTATION (% UT) NO 715487 3630 3645 124655124670 ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 34 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)716524 4443 4458 125468 125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 59 392A_(ds)A_(ds) ^(m)C_(ds)T_(ks)G_(ks)G_(k) 958499 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 15 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 958590 4439 4454 125464 125479AGGTATAACTGGGCAA A_(ks)G_(ks)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds) 18 905 G_(ds)G_(ds)G_(ds) ^(m)C_(ks)A_(ks)A_(k) 10093954442 4457 125467 125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 43 2801A_(ds) ^(m)C_(ds)T_(ds)G_(ks)G_(ks)G_(k) 1009396 4444 4459 106028 106043CACTGAGGTATAACTG ^(m)C_(ks)A_(ks)^(m)C_(ks)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 41 2802 125469 125484A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ks)T_(ks)G_(k) 1009397 4446 4461 106030106045 AACACTGAGGTATAAC A_(ks)A_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 44 2816 125471 125486G_(ds)T_(ds)A_(ds)T_(ds)A_(ks)A_(ks) ^(m)C_(k) 1074461 2529 2544 123554123569 GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 20 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1074726 4438 4453 125463 125478 GGTATAACTGGGCAAAG_(ks)G_(ks)T_(ks)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ds) 231427 G_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)A_(k) 1074727 4440 4455 125465125480 GAGGTATAACTGGGCAG_(ks)A_(ks)G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) 511503 T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074728 4441 4456 125466125481 TGAGGTATAACTGGGCT_(ks)G_(ks)A_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 141580 C_(ds)T_(ds)G_(ds)G_(ks)G_(ks) ^(m)C_(k) 1076439 N/A N/A 115906115921 CTTATATGGTTTTGTG^(m)C_(ks)T_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 31 2788T_(ds)T_(ds)T_(ds)G_(ks)T_(ks)G_(k) 1076456 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 44 1634T_(ds)A_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 1097224 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 22 2842G_(ds)G_(ds)T_(ds)T_(ds)T_(ks)T_(ks)G_(k) 1097247 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(ks)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 9 2867G_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(k) 1197199 N/A N/A 115903 115918ATATGGTTTTGTGTGTA_(ks)T_(ks)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 75 2839G_(ds)T_(ds)G_(ds)T_(ks)G_(ks)T_(k) 1197200 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(ks)A_(ks)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 49 2840T_(ds)T_(ds)G_(ds)T_(ks)G_(ks)T_(k) 1197201 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 46 2841T_(ds)T_(ds)T_(ds)T_(ks)G_(ks)T_(k) 1197202 N/A N/A 115909 115924ACTCTTATATGGTTTT A_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 27 2859T_(ds)G_(ds)G_(ds)T_(ds)T_(ks)T_(ks)T_(k) 1197203 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 68 2860A_(ds)T_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1197204 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(ks)A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 89 2861T_(ds)A_(ds)T_(ds)G_(ds)G_(ks)T_(ks)T_(k) 1197205 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(ks) ^(m)C_(ks)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds) 67 2862 T_(ds)A_(ds)T_(ds)A_(ds)T_(ks)G_(ks)G_(k)1197213 N/A N/A 117755 117770 TGTATGTCAGAAGAGTT_(ks)G_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds) 5 2863A_(ds)A_(ds)G_(ds)A_(ks)G_(ks)T_(k) 1197214 N/A N/A 117757 117772AGTGTATGTCAGAAGA A_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds) 5 2864 A_(ds)G_(ds)A_(ds)A_(ks)G_(ks)A_(k) 1197215 N/A N/A117758 117773 AAGTGTATGTCAGAAGA_(ks)A_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 132865 C_(ds)A_(ds)G_(ds)A_(ks)A_(ks)G_(k) 1197216 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 12 2866T_(ds) ^(m)C_(ds)A_(ds)G_(ks)A_(ks)A_(k) 1197217 N/A N/A 117761 117776TTAAAGTGTATGTCAG T_(ks)T_(ks)A_(ks)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)8 2868 T_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(k) 1197218 N/A N/A 117762117777 TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 29 2869A_(ds)T_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1197219 N/A N/A 117765 117780AACTTTAAAGTGTATG A_(ks)A_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) 71 2870T_(ds)G_(ds)T_(ds)A_(ks)T_(ks)G_(k) 1198284 2524 2539 123549 123564TGTCTCATGCCTTATA T_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m) 27 2803 C_(ds)^(m)C_(ds)T_(ds)T_(ks)A_(es)T_(ks)A_(e) 1198285 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds) 13 2804 T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ks)T_(es)T_(ks)A_(e) 1198286 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ks)T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 17 2805 A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(e)1198287 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(ks)A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 13 443C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(es) ^(m)C_(ks)T_(e) 1198288 2529 2544123554 123569 GAAATTGTCTCATGCCG_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)10 2800 C_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks) ^(m)C_(e) 1198289 2530 2545123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 122806 T_(ds) ^(m)C_(ds)A_(ks)T_(es)G_(ks) ^(m)C_(e) 1198290 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 152807 C_(ds)T_(ds) ^(m)C_(ks)A_(es)T_(ks)G_(e) 1198291 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 58 2808T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)A_(ks)T_(e) 1198292 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 58 656T_(ds)G_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e) 1198293 2560 2575 123585123600 AGTATGTGGCAATAATA_(ks)G_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) 252809 A_(ds)A_(ds)T_(ks)A_(es)A_(ks)T_(e) 1198294 2562 2577 123587 123602AGAGTATGTGGCAATAA_(ks)G_(ks)A_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 13 2810G_(ds) ^(m)C_(ds)A_(ks)A_(es)T_(ks)A_(e) 1198295 2563 2578 123588 123603TAGAGTATGTGGCAATT_(ks)A_(ks)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 15 2811G_(ds)G_(ds) ^(m)C_(ks)A_(es)A_(ks)T_(e) 1198296 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 29 963T_(ds)G_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(e) 1198297 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 8 810G_(ds)T_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(e) 1198298 2566 2581 123591 123606TATTAGAGTATGTGGCT_(ks)A_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 23 2812T_(ds)G_(ds)T_(ks)G_(es)G_(ks) ^(m)C_(e) 1198299 2567 2582 123592 123607ATATTAGAGTATGTGG A_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)27 2813 A_(ds)T_(ds)G_(ks)T_(es)G_(ks)G_(e) 1198300 2568 2583 123593123608 TATATTAGAGTATGTGT_(ks)A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 60 2814T_(ds)A_(ds)T_(ks)G_(es)T_(ks)G_(e) 1198301 2570 2585 123595 123610TCTATATTAGAGTATG T_(ks)^(m)C_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 43 887A_(ds)G_(ds)T_(ks)A_(es)T_(ks)G_(e) 1198307 4595 4610 125620 125635TTACATTAGGAACAAG T_(ks)T_(ks)A_(ks)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 49 2817 A_(ds)A_(ds)^(m)C_(ks)A_(es)A_(ks)G_(e) 1198308 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ks)T_(ks)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 68 2818 G_(ds)G_(ds)A_(ks)A_(es)^(m)C_(ks)A_(e) 1198309 4598 4613 125623 125638 CTTTTACATTAGGAAC^(m)C_(ks)T_(ks)T_(ks)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) 851124 A_(ds)G_(ds)G_(ks)A_(es)A_(ks) ^(m)C_(e) 1198310 4599 4614 125624125639 ACTTTTACATTAGGAA A_(ks) ^(m)C_(ks)T_(ks)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 28 2819 T_(ds)T_(ds)A_(ds)G_(ks)G_(es)A_(ks)A_(e)1198311 4600 4615 125625 125640 CACTTTTACATTAGGA ^(m)C_(ks)A_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 39 1200A_(ds)T_(ds)T_(ds)A_(ks)G_(es)G_(ks)A_(e) 1198312 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks) ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 7 1276C_(ds)A_(ds)T_(ds)T_(ks)A_(es)G_(ks)G_(e) 1198313 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 31 2820 A_(ds)^(m)C_(ds)A_(ds)T_(ks)T_(es)A_(ks)G_(e) 1198314 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(ks)G_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 82 2821 T_(ds)A_(ds)^(m)C_(ds)A_(ks)T_(es)T_(ks)A_(e) 1198315 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ks)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 85 2822 T_(ds)T_(ds)T_(ds)A_(ks) ^(m)C_(es)A_(ks)T_(e)1198316 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ks)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) 492823 A_(ds)A_(ds)A_(ks) ^(m)C_(es)T_(ks) ^(m)C_(e) 1198317 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 742824 T_(ds)G_(ds)A_(ks)A_(es)A_(ks) ^(m)C_(e) 1198318 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 1202825 C_(ds)T_(ds)G_(ks)A_(es)A_(ks)A_(e) 1198319 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ks)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 47 2826T_(ds) ^(m)C_(ds)T_(ks)G_(es)A_(ks)A_(e) 1198320 4800 4815 125825 125840GCTTTGGAAGATCTGA G_(ks)^(m)C_(ks)T_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 26 2044A_(ds)T_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(e) 1198321 4801 4816 125826 125841TGCTTTGGAAGATCTG T_(ks)G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 45 2121G_(ds)A_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(e) 1198322 4802 4817 125827 125842GTGCTTTGGAAGATCT G_(ks)T_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) 48 2827A_(ds)G_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(e) 1198323 4803 4818 125828 125843AGTGCTTTGGAAGATC A_(ks)G_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 32 2828A_(ds)A_(ds)G_(ks)A_(es)T_(ks) ^(m)C_(e) 1198324 4805 4820 125830 125845ATAGTGCTTTGGAAGA A_(ks)T_(ks)A_(ks)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 53 2829 G_(ds)G_(ds)A_(ks)A_(es)G_(ks)A_(e)1198325 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ks)G_(ks)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds) 342830 G_(ds)T_(ds)T_(ks)T_(es)T_(ks)T_(e) 1198326 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ks)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 84 2831 T_(ds)G_(ds)G_(ks)T_(es)T_(ks)T_(e) 1198327 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 292832 A_(ds)T_(ds)G_(ks)G_(es)T_(ks)T_(e) 1198328 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ks)T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 422833 C_(ds)A_(ds)T_(ks)G_(es)G_(ks)T_(e) 1198329 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(ks)T_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 36 2834G_(ds) ^(m)C_(ds)A_(ks)T_(es)G_(ks)G_(e) 1198330 N/A N/A 94735 94750AGATTTAGGATGCATGA_(ks)G_(ks)A_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 27 2934T_(ds)G_(ds) ^(m)C_(ks)A_(es)T_(ks)G_(e) 1198331 N/A N/A 94736 94751CAGATTTAGGATGCAT^(m)C_(ks)A_(ks)G_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 26 2836A_(ds)T_(ds)G_(ks) ^(m)C_(es)A_(ks)T_(e) 1198332 N/A N/A 94737 94752TCAGATTTAGGATGCA T_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 58 2837G_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks)A_(e) 1198333 N/A N/A 94739 94754ATTCAGATTTAGGATG A_(ks)T_(ks)T_(ks)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds) 77 2838A_(ds)G_(ds)G_(ks)A_(es)T_(ks)G_(e) 1198343 N/A N/A 117325 117340ATTGCAATCTGTCTGA A_(ks)T_(ks)T_(ks)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 39 2843 T_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(e)1198344 N/A N/A 117327 117342 ATATTGCAATCTGTCTA_(ks)T_(ks)A_(ks)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m)55 2844 C_(ds)T_(ds)G_(ks)T_(es) ^(m)C_(ks)T_(e) 1198345 N/A N/A 117328117343 AATATTGCAATCTGTC A_(ks)A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds) 75 2845 T_(ds) ^(m)C_(ds)T_(ks)G_(es)T_(ks)^(m)C_(e) 1198346 N/A N/A 117329 117344 TAATATTGCAATCTGTT_(ks)A_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 402846 A_(ds)T_(ds) ^(m)C_(ks)T_(es)G_(ks)T_(e) 1198347 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 141404 A_(ds)A_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(e) 1198348 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 402847 C_(ds)A_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(e)

TABLE 49Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ    ID ID SEQ ID SEQ ID YAP1 NO: 1 NO: 1 NO: 2 NO: 2 SEQ SEQCompound Start Stop Start Stop YAP1 ID Number Site Site Site SiteSequence (5' to 3') CHEMSITRY NOTATION (% UT) NO 715487 3630 3645 124655124670 ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 30 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(ks)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 13 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 10 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1095547 4443 4458 125468 125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 42 392A_(ds)A_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(e) 1095565 4441 4456 125466 125481TGAGGTATAACTGGGCT_(ks)G_(ks)A_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 251580 C_(ds)T_(ds)G_(ks)G_(es)G_(ks) ^(m)C_(e) 1095566 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)A_(ds) ^(m) 47 2801A_(ds) ^(m)C_(ds)T_(ks)G_(es)G_(ks)G_(e) 1095567 4444 4459 125469 125484CACTGAGGTATAACTG ^(m)C_(ks)A_(ks)^(m)C_(ks)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 92 2802A_(ds)T_(ds)A_(ds)A_(ks) ^(m)C_(es)T_(ks)G_(e) 1198302 4436 4451 125461125476 TATAACTGGGCAAATT T_(ks)A_(ks)T_(ks)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m) 67 2815C_(ds)A_(ds)A_(ks)A_(es)T_(ks)T_(e) 1198303 4438 4453 125463 125478GGTATAACTGGGCAAA G_(ks)G_(ks)T_(ks)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds) 27 1427 G_(ds)G_(ds) ^(m)C_(ks)A_(es)A_(ks)A_(e)1198304 4439 4454 125464 125479 AGGTATAACTGGGCAAA_(ks)G_(ks)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) 33 905G_(ds)G_(ds)G_(ks) ^(m)C_(es)A_(ks)A_(e) 1198305 4440 4455 125465 125480GAGGTATAACTGGGCA G_(ks)A_(ks)G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds) 78 1503 T_(ds)G_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(e) 1198306 44464461 125471 125486 AACACTGAGGTATAAC A_(ks)A_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 64 2816G_(ds)T_(ds)A_(ds)T_(ks)A_(es)A_(ks) ^(m)C_(e) 1198334 N/A N/A 115903115918 ATATGGTTTTGTGTGTA_(ks)T_(ks)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 57 2839G_(ds)T_(ds)G_(ks)T_(es)G_(ks)T_(e) 1198335 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(ks)A_(ks)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 26 2840T_(ds)T_(ds)G_(ks)T_(es)G_(ks)T_(e) 1198336 N/A N/A 115906 115921CTTATATGGTTTTGTG^(m)C_(ks)T_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 31 2788T_(ds)T_(ds)T_(ks)G_(es)T_(ks)G_(e) 1198337 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 26 2841T_(ds)T_(ds)T_(ks)T_(es)G_(ks)T_(e) 1198338 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 24 2842G_(ds)G_(ds)T_(ds)T_(ks)T_(es)T_(ks)G_(e) 1198339 N/A N/A 115909 115924ACTCTTATATGGTTTT A_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 25 2859T_(ds)G_(ds)G_(ds)T_(ks)T_(es)T_(ks)T_(e) 1198340 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 123 2860A_(ds)T_(ds)G_(ds)G_(ks)T_(es)T_(ks)T_(e) 1198341 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(ks)A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 90 2861T_(ds)A_(ds)T_(ds)G_(ks)G_(es)T_(ks)T_(e) 1198342 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(ks) ^(m)C_(ks)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds) 101 2862 T_(ds)A_(ds)T_(ds)A_(ks)T_(es)G_(ks)G_(e)1198349 N/A N/A 117332 117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds+ Ads)T_(ds)T_(ds) 85 2848G_(ds) ^(m)C_(ds)A_(ks)A_(es)T_(ks) ^(m)C_(e) 1198350 N/A N/A 117333117348 TATGTAATATTGCAATT_(ks)A_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 83 2849T_(ds)G_(ds) ^(m)C_(ks)A_(es)A_(ks)T_(e) 1198351 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 40 2850A_(ds)T_(ds)T_(ks)G_(es) ^(m)C_(ks)A_(e) 1198352 N/A N/A 117755 117770TGTATGTCAGAAGAGT T_(ks)G_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds)G_(ds) 7 2863 A_(ds)A_(ds)G_(ks)A_(es)G_(ks)T_(e)1198353 N/A N/A 117757 117772 AGTGTATGTCAGAAGAA_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 8 2864A_(ds)G_(ds)A_(ks)A_(es)G_(ks)A_(e) 1198354 N/A N/A 117758 117773AAGTGTATGTCAGAAGA_(ks)A_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 6 2865C_(ds)A_(ds)G_(ks)A_(es)A_(ks)G_(e) 1198355 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 6 2866T_(ds) ^(m)C_(ds)A_(ks)G_(es)A_(ks)A_(e) 1198356 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(ks)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 5 2867G_(ds)T_(ds) ^(m)C_(ks)A_(es)G_(ks)A_(e) 1198357 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks)T_(ks)A_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 21 2868T_(ds)G_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(e) 1198358 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 15 2869A_(ds)T_(ds)G_(ks)T_(es) ^(m)C_(ks)A_(e) 1198359 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 28 1634T_(ds)A_(ds)T_(ks)G_(es)T_(ks) ^(m)C_(e) 1198360 N/A N/A 117765 117780AACTTTAAAGTGTATG A_(ks)A_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) 74 2870T_(ds)G_(ds)T_(ks)A_(es)T_(ks)G_(e) 1198361 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(ks)A_(ks)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 39 2851 C_(ds) ^(m)C_(ds)A_(ds)G_(ks)A_(es)T_(ks)T_(e)1198362 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ks)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 242852 C_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)G_(ks)A_(e) 1198363 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 55 2853T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(e) 1198364 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 29 2854T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(e) 1198365 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds) 13 1101T_(ds)T_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(e) 1198366 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 45 2855G_(ds)T_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(e) 1198367 N/A N/A 119674119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 58 2856G_(ds)G_(ds)T_(ks)T_(es)T_(ks) ^(m)C_(e) 1198368 N/A N/A 119675 119690AGACTAAGTAAGGTTT A_(ks)G_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 79 2857A_(ds)G_(ds)G_(ks)T_(es)T_(ks)T_(e) 1198369 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(ks)A_(ks)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 51 2858T_(ds)A_(ds)A_(ks)G_(es)G_(ks)T_(e) 1198542 2524 2539 123549 123564TGTCTCATGCCTTATA T_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m) 23 2803 C_(ds)^(m)C_(ds)T_(ds)T_(ks)A_(ks)T_(ks)A_(e) 1198543 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(ks)T_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds) 15 2804 T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ks)T_(ks)T_(ks)A_(e) 1198544 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ks)T_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 21 2805 A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(ks)T_(e)1198545 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(ks)A_(ks)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 32 443C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(e) 1198546 2529 2544123554 123569 GAAATTGTCTCATGCCG_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)11 2800 C_(ds)A_(ds)T_(ks)G_(ks) ^(m)C_(ks) ^(m)C_(e) 1198547 2530 2545123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 272806 T_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(ks) ^(m)C_(e) 1198548 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 262807 C_(ds)T_(ds) ^(m)C_(ks)A_(ks)T_(ks)G_(e) 1198549 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 84 2808T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)A_(ks)T_(e) 1198550 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ks)TasG_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 17 656T_(ds)G_(ds)T_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(e) 1198551 2560 2575 123585123600 AGTATGTGGCAATAATA_(ks)G_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) 342809 A_(ds)A_(ds)T_(ks)A_(ks)A_(ks)T_(e) 1198552 2562 2577 123587 123602AGAGTATGTGGCAATAA_(ks)G_(ks)A_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 17 2810G_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(ks)A_(e) 1198553 2563 2578 123588 123603TAGAGTATGTGGCAATT_(ks)A_(ks)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 13 2811G_(ds)G_(ds) ^(m)C_(ks)A_(ks)A_(ks)T_(e) 1198554 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 16 963T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(ks)A_(e) 1198555 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 11 810G_(ds)T_(ds)G_(ks)G_(ks) ^(m)C_(ks)A_(e) 1198556 2566 2581 123591 123606TATTAGAGTATGTGGCT_(ks)A_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 25 2812T_(ds)G_(ds)T_(ks)G_(ks)G_(ks) ^(m)C_(e) 1198557 2567 2582 123592 123607ATATTAGAGTATGTGGA_(ks)T_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 16 2813A_(ds)T_(ds)G_(ks)T_(ks)G_(ks)G_(e) 1198558 2568 2583 123593 123608TATATTAGAGTATGTGT_(ks)A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 46 2814T_(ds)A_(ds)T_(ks)G_(ks)T_(ks)G_(e) 1198559 2570 2585 123595 123610TCTATATTAGAGTATG T_(ks)^(m)C_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 55 887A_(ds)G_(ds)T_(ks)A_(ks)T_(ks)G_(e) 1198565 4595 4610 125620 125635TTACATTAGGAACAAG T_(ks)T_(ks)A_(ks)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 53 2817 A_(ds)A_(ds)^(m)C_(ks)A_(ks)A_(ks)G_(e) 1198566 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ks)T_(ks)T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 83 2818 G_(ds)G_(ds)A_(ks)A_(ks)^(m)C_(ks)A_(e) 1198567 4598 4613 125623 125638 CTTTTACATTAGGAAC^(m)C_(ks)T_(ks)T_(ks)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) 541124 A_(ds)G_(ds)G_(ks)A_(ks)A_(ks) ^(m)C_(e) 1198568 4599 4614 125624125639 ACTTTTACATTAGGAA A_(ks) ^(m)C_(ks)T_(ks)T_(ds)T_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 31 2819 T_(ds)T_(ds)A_(ds)G_(ks)G_(ks)A_(ks)A_(e)1198569 4600 4615 125625 125640 CACTTTTACATTAGGA ^(m)C_(ks)A_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 14 1200A_(ds)T_(ds)T_(ds)A_(ks)G_(ks)G_(ks)A_(e) 1198570 4601 4616 125626125641 GCACTTTTACATTAGG G_(ks) ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 15 1276C_(ds)A_(ds)T_(ds)T_(ks)A_(ks)G_(ks)G_(e) 1198571 4602 4617 125627125642 AGCACTTTTACATTAG A_(ks)G_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 32 2820 A_(ds)^(m)C_(ds)A_(ds)T_(ks)T_(ks)A_(ks)G_(e) 1198572 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(ks)G_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 53 2821 T_(ds)A_(ds)^(m)C_(ds)A_(ks)T_(ks)T_(ks)A_(e) 1198573 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ks)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 76 2822 T_(ds)T_(ds)T_(ds)A_(ks) ^(m)C_(ks)A_(ks)T_(e)1198574 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ks)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) 372823 A_(ds)A_(ds)A_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(e) 1198575 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 942824 T_(ds)G_(ds)A_(ks)A_(ks)A_(ks) ^(m)C_(e) 1198576 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 922825 C_(ds)T_(ds)G_(ks)A_(ks)A_(ks)A_(e) 1198577 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ks)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 40 2826T_(ds) ^(m)C_(ds)T_(ks)G_(ks)A_(ks)A_(e) 1198578 4800 4815 125825 125840GCTTTGGAAGATCTGA^(m)C_(ks)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 18 2044A_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(ks)A_(e) 1198579 4801 4816 125826 125841TGCTTTGGAAGATCTG T_(ks)G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 34 2121G_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(ks)G_(e) 1198580 4802 4817 125827 125842GTGCTTTGGAAGATCT G_(ks)T_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds) 43 2827A_(ds)G_(ds)A_(ks)T_(ks) ^(m)C_(ks)T_(e) 1198581 4803 4818 125828 125843AGTGCTTTGGAAGATC A_(ks)G_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 42 2828A_(ds)A_(ds)G_(ks)A_(ks)T_(ks) ^(m)C_(e) 1198582 4805 4820 125830 125845ATAGTGCTTTGGAAGA A_(ks)T_(ks)A_(ks)G_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 63 2829 G_(ds)G_(ds)A_(ks)A_(ks)G_(ks)A_(e)1198583 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ks)G_(ks)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds) 272830 G_(ds)T_(ds)T_(ks)T_(ks)T_(ks)T_(e) 1198584 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ks)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds) 37 2831 T_(ds)G_(ds)G_(ks)T_(ks)T_(ks)T_(e)

TABLE 50Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ   ID ID SEQ ID SEQ ID YAP1  NO: 1 NO: 1 NO: 2 NO: 2 SEQ SEQCompound Start Stop Start Stop YAP1 ID Number Site Site Site SiteSequence (5' to 3') CHEMSITRY NOTATION (% UT) NO 715487 3630 3645 124655124670 ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 31 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 12 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 16 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1095435 4443 4458 125468 125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 39 392A_(ds)A_(ds) ^(m)C_(ks)T_(ks)G_(ks)G_(e) 1095453 4441 4456 125466 125481TGAGGTATAACTGGGCT_(ks)G_(ks)A_(ks)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 321580 C_(ds)T_(ds)G_(ks)G_(ks)G_(ks) ^(m)C_(e) 1095454 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 47 2801A_(ds) ^(m)C_(ds)T_(ks)G_(ks)G_(ks)G_(e) 1197228 2527 2542 123552 123567AATTGTCTCATGCCTT A_(ks)A_(ks)T_(ks)T_(ds)G_(ys)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 25 2805 A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)T_(k)1197229 2530 2545 123555 123570 GGAAATTGTCTCATGCG_(ks)G_(ks)A_(ks)A_(ds)A_(ys)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 212806 T_(ds) ^(m)C_(ds)A_(ds)T_(ks)G_(ks) ^(m)C_(k) 1197230 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ks)A_(ds)A_(ys)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 292807 C_(ds)T_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(k) 1197231 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ks)G_(ds)A_(ys)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 50 2808T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)A_(ks)T_(k) 1197232 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ks)T_(ds)G_(ys)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 55 656T_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 1197233 2563 2578 123588123603 TAGAGTATGTGGCAATT_(ks)A_(ks)G_(ks)A_(ds)G_(ys)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 36 2811G_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(k) 1197234 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ks)G_(ds)A_(ys)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 24 963T_(ds)G_(ds)G_(ds) ^(m)C_(ks)A_(ks)A_(k) 1197235 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ys)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 16 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1197236 2566 2581 123591 123606TATTAGAGTATGTGGCT_(ks)A_(ks)T_(ks)T_(ds)A_(ys)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 17 2812T_(ds)G_(ds)T_(ds)G_(ks)G_(ks) ^(m)C_(k) 1197244 4595 4610 125620 125635TTACATTAGGAACAAG T_(ks)T_(ks)A_(ks)^(m)C_(ds)A_(ys)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 60 2817 A_(ds)A_(ds)^(m)C_(ds)A_(ks)A_(ks)G_(k) 1197245 4597 4612 125622 125637TTTTACATTAGGAACA T_(ks)T_(ks)T_(ks)T_(ds)A_(ys)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 60 2818 G_(ds)G_(ds)A_(ds)A_(ks)^(m)C_(ks)A_(k) 1197246 4602 4617 125627 125642 AGCACTTTTACATTAGA_(ks)G_(ks) ^(m)C_(ks)A_(ds)C_(ys)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)33 2820 C_(ds)A_(ds)T_(ds)T_(ks)A_(ks)G_(k) 1197247 4603 4618 125628125643 AAGCACTTTTACATTA A_(ks)A_(ks)G_(ks) ^(m)C_(ds)A_(ys)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 47 2821 T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ks)T_(ks)A_(k) 1197280 2524 2539 123549 123564TGTCUCATGCCTTATA T_(ks)G_(ks)T_(ks) ^(m)C_(ds)U_(ys)^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m) 53 2871 C_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ks)T_(ks)A_(k) 1197281 2526 2541 123551 123566ATTGUCTCATGCCTTA A_(ks)T_(ks)T_(ks)G_(ds)U_(ys)^(m)C_(ds)T_(ds)C_(ds)A_(ds) 42 2872 T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)T_(ks)A_(k) 1197282 2528 2543 123553 123568AAATUGTCTCATGCCT A_(ks)A_(ks)A_(ks)T_(ds)U_(ys)G_(ds) ^(m)C_(ds)T_(ds)^(m) 40 2873 C_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 11972832529 2544 123554 123569 GAAAUTGTCTCATGCCG_(ks)A_(ks)A_(ks)A_(ds)U_(ys)T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)29 2874 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(k) 1197284 2560 2575123585 123600 AGTAUGTGGCAATAATA_(ks)G_(ks)T_(ks)A_(ds)U_(ys)G_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) 352875 A_(ds)A_(ds)T_(ds)A_(ks)A_(ks)T_(k) 1197285 2562 2577 123587 123602AGAGUATGTGGCAATAA_(ks)G_(ks)A_(ks)G_(ds)U_(ys)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 28 2876G_(ds) ^(m)C_(ds)A_(ds)A_(ks)T_(ks)A_(k) 1197286 2567 2582 123592 123607ATATUAGAGTATGTGGA_(ks)T_(ks)A_(ks)T_(ds)U_(ys)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 43 2877A_(ds)T_(ds)G_(ds)T_(ks)G_(ks)G_(k) 1197287 2568 2583 123593 123608TATAUTAGAGTATGTGT_(ks)A_(ks)T_(ks)A_(ds)U_(ys)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 108 2878T_(ds)A_(ds)T_(ds)G_(ks)T_(ks)G_(k) 1197288 2570 2585 123595 123610TCTAUATTAGAGTATG T_(ks)^(m)C_(ks)T_(ks)A_(ds)U_(ys)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 94 2879A_(ds)G_(ds)T_(ds)A_(ks)T_(ks)G_(k) 1197291 4598 4613 125623 125638CTTTUACATTAGGAAC ^(m)C_(ks)T_(ks)T_(ks)T_(ds)U_(ys)A_(ds)^(m)C_(ds)A_(ds)T_(ds) 83 2880 T_(ds)A_(ds)G_(ds)G_(ds)A_(ks)A_(ks)^(m)C_(k) 1197292 4599 4614 125624 125639 ACTTUTACATTAGGAA A_(ks)^(m)C_(ks)T_(ks)T_(ds)U_(ys)T_(ds)A_(ds) ^(m)C_(ds)A_(ds) 84 2881T_(ds)T_(ds)A_(ds)G_(ds)G_(ks)A_(ks)A_(k) 1197293 4600 4615 125625125640 CACTUTTACATTAGGA ^(m)C_(ks)A_(ks)^(m)C_(ks)T_(ds)U_(ys)T_(ds)T_(ds)A_(ds) ^(m)C_(ds) 94 2882A_(ds)T_(ds)T_(ds)A_(ds)G_(ks)G_(ks)A_(k) 1197294 4601 4616 125626125641 GCACUTTTACATTAGG G_(ks) ^(m)C_(ks)A_(ks)^(m)C_(ds)U_(ys)T_(ds)T_(ds)T_(ds)A_(ds) ^(m) 25 2883C_(ds)A_(ds)T_(ds)T_(ds)A_(ks)G_(ks)G_(k) 1198560 4436 4451 125461125476 TATAACTGGGCAAATT T_(ks)A_(ks)T_(ks)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m) 53 2815C_(ds)A_(ds)A_(ks)A_(ks)T_(ks)T_(e) 1198561 4438 4453 125463 125478GGTATAACTGGGCAAA G_(ks)G_(ks)T_(ks)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds) 29 1427 G_(ds)G_(ds) ^(m)C_(ks)A_(ks)A_(ks)A_(e)1198562 4439 4454 125464 125479 AGGTATAACTGGGCAAA_(ks)G_(ks)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) 30 905G_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(ks)A_(e) 1198563 4440 4455 125465 125480GAGGTATAACTGGGCA G_(ks)A_(ks)G_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds) 53 1503 T_(ds)G_(ds)G_(ks)G_(ks) ^(m)C_(ks)A_(e) 1198564 44464461 125471 125486 AACACTGAGGTATAAC A_(ks)A_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)G 44 2816 G_(ds)T_(ds)A_(ds)T_(ks)A_(ks)A_(ks) ^(m)C_(e)1198585 N/A N/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 222832 A_(ds)T_(ds)G_(ks)G_(ks)T_(ks)T_(e) 1198586 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ks)T_(ks)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 962833 C_(ds)A_(ds)T_(ks)G_(ks)G_(ks)T_(e) 1198587 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(ks)T_(ks)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 41 2834G_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(ks)G_(e) 1198588 N/A N/A 94735 94750AGATTTAGGATGCATGA_(ks)G_(ks)A_(ks)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 32 2835T_(ds)G_(ds) ^(m)C_(ks)A_(ks)T_(ks)G_(e) 1198589 N/A N/A 94736 94751CAGATTTAGGATGCAT^(m)C_(ks)A_(ks)G_(ks)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 24 2836A_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(ks)T_(e) 1198590 N/A N/A 94737 94752TCAGATTTAGGATGCA T_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 46 2837G_(ds)A_(ds)T_(ks)G_(ks) ^(m)C_(ks)A_(e) 1198591 N/A N/A 94739 94754ATTCAGATTTAGGATG A_(ks)T_(ks)T_(ks)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds) 106 2838A_(ds)G_(ds)G_(ks)A_(ks)T_(ks)G_(e) 1198592 N/A N/A 115903 115918ATATGGTTTTGTGTGTA_(ks)T_(ks)A_(ks)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 50 2839G_(ds)T_(ds)G_(ks)T_(ks)G_(ks)T_(e) 1198593 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(ks)A_(ks)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 45 2840T_(ds)T_(ds)G_(ks)T_(ks)G_(ks)T_(e) 1198594 N/A N/A 115906 115921CTTATATGGTTTTGTG^(m)C_(ks)T_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 23 2788T_(ds)T_(ds)T_(ks)G_(ks)T_(ks)G_(e) 1198595 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 27 2841T_(ds)T_(ds)T_(ks)T_(ks)G_(ks)T_(e) 1198596 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 16 2842G_(ds)G_(ds)T_(ds)T_(ks)T_(ks)T_(ks)G_(e) 1198597 N/A N/A 115909 115924ACTCTTATATGGTTTT A_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 27 2859T_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(ks)T_(e) 1198598 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 76 2860A_(ds)T_(ds)G_(ds)G_(ks)T_(ks)T_(ks)T_(e) 1198599 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(ks)A_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 90 2861T_(ds)A_(ds)T_(ds)G_(ks)G_(ks)T_(ks)T_(e) 1198600 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(ks) ^(m)C_(ks)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds) 72 2862 T_(ds)A_(ds)T_(ds)A_(ks)T_(ks)G_(ks)G_(e)1198601 N/A N/A 117325 117340 ATTGCAATCTGTCTGA A_(ks)T_(ks)T_(ks)G_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) 50 2843 T_(ds)G_(ds)T_(ds)^(m)C_(ks)T_(ks)G_(ks)A_(e) 1198602 N/A N/A 117327 117342ATATTGCAATCTGTCT A_(ks)T_(ks)A_(ks)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m) 29 2844 C_(ds)T_(ds)G_(ks)T_(ks)^(m)C_(ks)T_(e) 1198603 N/A N/A 117328 117343 AATATTGCAATCTGTCA_(ks)A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) 512845 T_(ds) ^(m)C_(ds)T_(ks)G_(ks)T_(ks) ^(m)C_(e) 1198604 N/A N/A117329 117344 TAATATTGCAATCTGTT_(ks)A_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 482846 A_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(ks)T_(e) 1198605 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 7 1404A_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(ks)G_(e) 1198606 N/A N/A 117331 117346TGTAATATTGCAATCTT_(ks)G_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 252847 C_(ds)A_(ds)A_(ks)T_(ks) ^(m)C_(ks)T_(e) 1198607 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 77 2848G_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(ks)mC_(e) 1198608 N/A N/A 117333 117348TATGTAATATTGCAATT_(ks)A_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 83 2849T_(ds)G_(ds) ^(m)C_(ks)A_(ks)A_(ks)T_(e) 1198609 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 52 2850A_(ds)T_(ds)T_(ks)G_(ks) ^(m)C_(ks)A_(e) 1198610 N/A N/A 117755 117770TGTATGTCAGAAGAGT T_(ks)G_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds)G_(ds)4 2863 A_(ds)A_(ds)G_(ks)A_(ks)G_(ks)T_(e) 1198611N/A N/A 117757 117772 AGTGTATGTCAGAAGAA_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 7 2864A_(ds)G_(ds)A_(ks)A_(ks)G_(ks)A_(e) 1198612 N/A N/A 117758 117773AAGTGTATGTCAGAAGA_(ks)A_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 5 2865C_(ds)A_(ds)G_(ks)A_(ks)A_(ks)G_(e) 1198613 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 3 2866T_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(ks)A_(e) 1198614 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(ks)A_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 4 2867G_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(ks)A_(e) 1198615 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks+lTks)A_(ks)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 10 2868T_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(ks)G_(e) 1198616 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 16 2869A_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(ks)A_(e) 1198617 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 34 1634T_(ds)A_(ds)T_(ks)G_(ks)T_(ks) ^(m)C_(e) 1198618 N/A N/A 117765 117780AACTTTAAAGTGTATG A_(ks)A_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) 74 2870T_(ds)G_(ds)T_(ks)A_(ks)T_(ks)G_(e) 1198619 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(ks)A_(ks)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 53 2851 C_(ds) ^(m)C_(ds)A_(ds)G_(ks)A_(ks)T_(ks)T_(e)1198620 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ks)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 262852 C_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(ks)A_(e) 1198621 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 80 2853T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)G_(e) 1198622 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 26 2854T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 1198623 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds) 9 1101T_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(e) 1198624 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 20 2855G_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(e) 1198625 N/A N/A 119674119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 64 2856G_(ds)G_(ds)T_(ks)T_(ks)T_(ks) ^(m)C_(e) 1198626 N/A N/A 119675 119690AGACTAAGTAAGGTTT A_(ks)G_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 99 2857A_(ds)G_(ds)G_(ks)T_(ks)T_(ks)T_(e) 1198627 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(ks)A_(ks)G_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 39 2858T_(ds)A_(ds)A_(ks)G_(ks)G_(ks)T_(e)

TABLE 51Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ    ID ID SEQ ID SEQ ID YAP1 NO: 1 NO: 1 NO: 2 NO: 2 SEQ SEQCompound Start Stop Start Stop YAP1 ID Number Site Site Site SiteSequence (5' to 3') CHEMSITRY NOTATION (% UT) NO 715487 3630 3645 124655124670 ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 24 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 9 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 5 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1197237 4436 4451 125461 125476 TATAACTGGGCAAATTT_(ks)A_(ks)T_(ks)A_(ds)A_(ys) ^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)74 2815 C_(ds)A_(ds)A_(ds)A_(ks)T_(ks)T_(k) 1197238 4439 4454 125464125479 AGGTATAACTGGGCAA A_(ks)G_(ks)G_(ks)T_(ds)A_(ys)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds) 43 905 G_(ds)G_(ds)G_(ds) ^(m)C_(ks)A_(ks)A_(k) 11972394441 4456 125466 125481 TGAGGTATAACTGGGCT_(ks)G_(ks)A_(ks)G_(ds)G_(ys)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 471580 C_(ds)T_(ds)G_(ds)G_(ks)G_(ks) ^(m)C_(k) 1197240 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ks)A_(ds)G_(ys)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 58 2801A_(ds) ^(m)C_(ds)T_(ds)G_(ks)G_(ks)G_(k) 1197241 4443 4458 125468 125483ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ks)G_(ds)A_(ys)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds+l) 19 392A_(ds)A_(ds) ^(m)C_(ds)T_(ks)G_(ks)G_(k) 1197242 4444 4459 125469 125484CACTGAGGTATAACTG ^(m)C_(ks)A_(ks)^(m)C_(ks)T_(ds)G_(ys)A_(ds)G_(ds)G_(ds)T_(ds) 46 2802A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ks)T_(ks)G_(k) 1197243 4446 4461 125471125486 AACACTGAGGTATAAC A_(ks)A_(ks)^(m)C_(ks)A_(ds)C_(ys)T_(ds)G_(ds)A_(ds)G_(ds) 81 2816G_(ds)T_(ds)A_(ds)T_(ds)A_(ks)A_(ks) ^(m)C_(k) 1197248 4605 4620 125630125645 TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ks)A_(ds)G_(ys) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) 75 2822 T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ks)T_(k)1197249 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ks)A_(ds)G_(ys)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)28 2823A_(ds)A_(ds)A_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 1197250 4797 4812 125822125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ks)G_(ds)A_(ys)A_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 602824 T_(ds)G_(ds)A_(ds)A_(ks)A_(ks) ^(m)C_(k) 1197251 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ks)G_(ds)G_(ys)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 742825 C_(ds)T_(ds)G_(ds)A_(ks)A_(ks)A_(k) 1197252 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ks)T_(ks)T_(ds)G_(ys)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 53 2826T_(ds) ^(m)C_(ds)T_(ds)G_(ks)A_(ks)A_(k) 1197253 4803 4818 125828 125843AGTGCTTTGGAAGATCA_(ks)G_(ks)T_(ks)G_(ds)C_(ys)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 58 2828A_(ds)A_(ds)G_(ds)A_(ks)T_(ks) ^(m)C_(k) 1197254 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ks)G_(ds)G_(ys)A_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 51 2831 T_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1197255 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ks)A_(ds)G_(ys)G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 382832 A_(ds)T_(ds)G_(ds)G_(ks)T_(ks)T_(k) 1197256 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ks)T_(ks)T_(ds)A_(ys)G_(ds)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 312833 C_(ds)A_(ds)T_(ds)G_(ks)G_(ks)T_(k) 1197257 N/A N/A 94737 94752TCAGATTTAGGATGCA T_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ys)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 20 2837G_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(k) 1197258 N/A N/A 94739 94754ATTCAGATTTAGGATG A_(ks+lTks)T_(ks)^(m)C_(ds)A_(ys)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds) 57 2838A_(ds)G_(ds)G_(ds)A_(ks)T_(ks)G_(k) 1197259 N/A N/A 115903 115918ATATGGTTTTGTGTGTA_(ks)T_(ks)A_(ks)T_(ds)G_(ys)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 59 2839G_(ds)T_(ds)G_(ds)T_(ks)G_(ks)T_(k) 1197260 N/A N/A 115905 115920TTATATGGTTTTGTGTT_(ks)T_(ks)A_(ks)T_(ds)A_(ys)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 65 2840T_(ds)T_(ds)G_(ds)T_(ks)G_(ks)T_(k) 1197261 N/A N/A 115907 115922TCTTATATGGTTTTGT T_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ys)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 91 2841T_(ds)T_(ds)T_(ds)T_(ks)G_(ks)T_(k) 1197262 N/A N/A 115910 115925AACTCTTATATGGTTT A_(ks)A_(ks)^(m)C_(ks)T_(ds)C_(ys)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 89 2860T_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1197263 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks) ^(m)A_(ks) ^(m)C_(ks)A_(ds)A_(ys)^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds) 91 2862T_(ds)A_(ds)T_(ds)A_(ds)T_(ks)G_(ks)G_(k) 1197264 N/A N/A 117325 117340ATTGCAATCTGTCTGA A_(ks)T_(ks)T_(ks)G_(ds)C_(ys)A_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds) 33 2843 G_(ds)T_(ds) ^(m)C_(ds)T_(ks)G_(ks)A_(k)1197265 N/A N/A 117329 117344 TAATATTGCAATCTGTT_(ks)A_(ks)A_(ks)T_(ds)A_(ys)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 1032846 A_(ds)T_(ds) ^(m)C_(ds)T_(ks)G_(ks)T_(k) 1197266 N/A N/A 117331117346 TGTAATATTGCAATCTT_(ks)G_(ks)T_(ks)A_(ds)A_(ys)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 312847 C_(ds)A_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(k) 1197267 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ks)T_(ds)A_(ys)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 62 2848G_(ds) ^(m)C_(ds)A_(ds)A_(ks)T_(ks) ^(m)C_(k) 1197268 N/A N/A 117758117773 AAGTGTATGTCAGAAGA_(ks)A_(ks)G_(ks)T_(ds)G_(ys)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 252865 C_(ds)A_(ds)G_(ds)A_(ks)A_(ks)G_(k) 1197269 N/A N/A 117760 117775TAAAGTGTATGTCAGAT_(ks)A_(ks)A_(ks)A_(ds)G_(ys)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 3 2867G_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(k) 1197270 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks)T_(ks)A_(ks)A_(ds)A_(ys)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 2 2868T_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(k) 1197271 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ks)A_(ds)A_(ys)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds) 12 2869A_(ds)T_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1197272 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ks)T_(ds)A_(ys)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 32 1634T_(ds)A_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 1197273 N/A N/A 119667 119682TAAGGTTTCCCAGATT T_(ks)A_(ks)A_(ks)G_(ds)G_(ys)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 68 2851 C_(ds) ^(m)C_(ds)A_(ds)G_(ds)A_(ks)T_(ks)T_(k)1197274 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ks)A_(ds)A_(ys)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 312852 C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(k) 1197275 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ks)T_(ds)A_(ys)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds) 30 2853T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(k) 1197276 N/A N/A119672 119687 CTAAGTAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ks)A_(ds)G_(ys)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds) 44 1101T_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(k) 1197277 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ks)A_(ds)A_(ys)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 23 2855G_(ds)T_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 1197278 N/A N/A 119674119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ks)T_(ds)A_(ys)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 36 2856G_(ds)G_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(k) 1197279 N/A N/A 119677 119692TTAGACTAAGTAAGGT T_(ks)T_(ks)A_(ks)G_(ds)A_(ys)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 54 2858T_(ds)A_(ds)A_(ds)G_(ks)G_(ks)T_(k) 1197289 4438 4453 125463 125478GGTAUAACTGGGCAAA G_(ks)G_(ks)T_(ks)A_(ds)U_(ys)A_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds) 48 2884 G_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)A_(k)1197290 4440 4455 125465 125480 GAGGUATAACTGGGCAG_(ks)A_(ks)G_(ks)G_(ds)U_(ys)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 37 2885C_(ds)T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1197295 4800 4815 125825125840 GCTTUGGAAGATCTGA G_(ks)^(m)C_(ks)T_(ks)T_(ds)U_(ys)G_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 24 2886A_(ds)T_(ds)C_(ds)T_(ks)G_(ks)A_(k) 1197296 4801 4816 125826 125841TGCTUTGGAAGATCTG T_(ks)G_(ks)^(m)C_(ks)T_(ds)U_(ys)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 36 2887G_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(k) 1197297 4802 4817 125827 125842GTGCUTTGGAAGATCT G_(ks)T_(ks)G_(ks)^(m)C_(ds)U_(ys)T_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 25 2888A_(ds)G_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(k) 1197298 4805 4820 125830 125845ATAGUGCTTTGGAAGA A_(ks)T_(ks)A_(ks)G_(ds)U_(ys)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 46 2889 G_(ds)G_(ds)A_(ds)A_(ks)G_(ks)A_(k)1197299 N/A N/A 94729 94744 AGGAUGCATGGTTTTTA_(ks)G_(ks)G_(ks)A_(ds)U_(ys)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) 41 2890G_(ds)G_(ds)T_(ds)T_(ds)T_(ks)T_(ks)T_(k) 1197300 N/A N/A 94734 94749GATTUAGGATGCATGGG_(ks)A_(ks)T_(ks)T_(ds)U_(ys)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 42 2891G_(ds) ^(m)C_(ds)A_(ds)T_(ks)G_(ks)G_(k) 1197301 N/A N/A 94735 94750AGATUTAGGATGCATG A_(ks)A_(ks)T_(ds)U_(ys)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)71 2892 T_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(k) 1197302 N/A N/A 9473694751 CAGAUTTAGGATGCAT^(m)C_(ks)A_(ks)G_(ks)A_(ds)U_(ys)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 54 2893A_(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(ks)T_(k) 1197303 N/A N/A 115906 115921CTTAUATGGTTTTGTG^(m)C_(ks)T_(ks)T_(ks)A_(ds)U_(ys)A_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 72 2894T_(ds)T_(ds)T_(ds)G_(ks)T_(ks)G_(k) 1197304 N/A N/A 115908 115923CTCTUATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ks)T_(ds)U_(ys)A_(ds)T_(ds)A_(ds)T_(ds) 45 2895G_(ds)G_(ds)T_(ds)T_(ds)T_(ks)T_(ks)G_(k) 1197305 N/A N/A 115909 115924ACTCUTATATGGTTTT A_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)U_(ys)T_(ds)A_(ds)T_(ds)A_(ds) 30 2896T_(ds)G_(ds)G_(ds)T_(ds)T_(ks)T_(ks)T_(k) 1197306 N/A N/A 115911 115926CAACUCTTATATGGTT ^(m)C_(ks)A_(ks)A_(ks) ^(m)C_(ds)U_(ys)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 77 2897T_(ds)A_(ds)T_(ds)G_(ds)G_(ks)T_(ks)T_(k) 1197307 N/A N/A 117327 117342ATATUGCAATCTGTCT A_(ks)T_(ks)A_(ks)T_(ds)U_(ys)G_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m) 88 2898 C_(ds)T_(ds)G_(ds)T_(ks)^(m)C_(ks)T_(k) 1197308 N/A N/A 117328 117343 AATAUTGCAATCTGTCA_(ks)A_(ks)T_(ks)A_(ds)U_(ys)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) 492899 T_(ds) ^(m)C_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 1197309 N/A N/A117330 117345 GTAAUATTGCAATCTGG_(ks)T_(ks)A_(ks)A_(ds)U_(ys)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 112900 A_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(k) 1197310 N/A N/A 117333117348 TATGUAATATTGCAATT_(ks)A_(ks)T_(ks)G_(ds)U_(ys)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 109 2901T_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(k) 1197311 N/A N/A 117335 117350TTTAUGTAATATTGCAT_(ks)T_(ks)T_(ks)A_(ds)U_(ys)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 27 2902A_(ds)T_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(k) 1197312 N/A N/A 117755 117770TGTAUGTCAGAAGAGT T_(ks)G_(ks)T_(ks)A_(ds)U_(ys)G_(ds)T_(ds)^(m)C_(ds)A_(ds)G_(ds) 10 2903 A_(ds)A_(ds)G_(ds)A_(ks)G_(ks)T_(k)1197313 N/A N/A 117757 117772 AGTGUATGTCAGAAGAA_(ks)G_(ks)T_(ks)G_(ds)U_(ys)A_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 8 2904A_(ds)G_(ds)A_(ds)A_(ks)G_(ks)A_(k) 1197314 N/A N/A 117759 117774AAAGUGTATGTCAGAAA_(ks)A_(ks)A_(ks)G_(ds)U_(ys)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 22 2905T_(ds) ^(m)C_(ds)A_(ds)G_(ks)A_(ks)A_(k) 1197315 N/A N/A 117765 117780AACTUTAAAGTGTATG A_(ks)A_(ks)^(m)C_(ks)T_(ds)U_(ys)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) 116 2906T_(ds)G_(ds)T_(ds)A_(ks)T_(ks)G_(k) 1197316 N/A N/A 119671 119686TAAGUAAGGTTTCCCAT_(ks)A_(ks)A_(ks)G_(ds)U_(ys)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 46 2907T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 1197317 N/A N/A119675 119690 AGACUAAGTAAGGTTT A_(ks)G_(ks)A_(ks)^(m)C_(ds)U_(ys)A_(ds)A_(ds)G_(ds)T_(ds) 78 2908A_(ds)A_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1200784 2524 2539 123549123564 TGTCTCATGCCTTATA T_(ks)G_(ks)T_(ks)^(m)C_(ds)T_(ds)C_(ys)A_(ds)T_(ds)G_(ds) ^(m) 19 2803 C_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ks)T_(ks)A_(k) 1200785 2526 2541 123551 123566ATTGTCTCATGCCTTA A_(ks)T_(ks)T_(ks)G_(ds)T_(ds)C_(ys)T_(ds)^(m)C_(ds)A_(ds)T_(ds) 15 2804 G_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)T_(ks)A_(k) 1200786 2527 2542 123552 123567AATTGUCTCATGCCTT A_(ks)A_(ks)T_(ks)T_(ds)G_(ds)U_(ys) ^(m)C_(ds)T_(ds)^(m)C_(ds) 21 2909 A_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)T_(k)1200787 2528 2543 123553 123568 AAATTGTCTCATGCCTA_(ks)A_(ks)A_(ks)T_(ds)T_(ds)G_(ys)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 38 443C_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 1200793 2560 2575123585 123600 AGTATGTGGCAATAATA_(ks)G_(ks)T_(ks)A_(ds)T_(ds)G_(ys)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) 312809 A_(ds)A_(ds)T_(ds)A_(ks)A_(ks)T_(k) 1200794 2562 2577 123587 123602AGAGTATGTGGCAATAA_(ks)G_(ks)A_(ks)G_(ds)T_(ds)A_(ys)T_(ds)G_(ds)T_(ds)G_(ds) 18 2810G_(ds) ^(m)C_(ds)A_(ds)A_(ks)T_(ks)A_(k) 1200795 2563 2578 123588 123603TAGAGUATGTGGCAATT_(ks)A_(ks)G_(ks)A_(ds)G_(ds)U_(ys)A_(ds)T_(ds)G_(ds)T_(ds) 30 2910G_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(k) 1200796 2564 2579 123589 123604TTAGAGTATGTGGCAAT_(ks)T_(ks)A_(ks)G_(ds)A_(ds)G_(ys)T_(ds)A_(ds)T_(ds)G_(ds) 15 963T_(ds)G_(ds)G_(ds) ^(m)C_(ks)A_(ks)A_(k) 1200797 2565 2580 123590 123605ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ys)G_(ds)T_(ds)A_(ds)T_(ds) 11 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1200798 2566 2581 123591 123606TATTAGAGTATGTGGCT_(ks)A_(ks)T_(ks)T_(ds)A_(ds)G_(ys)A_(ds)G_(ds)T_(ds)A_(ds) 7 2812T_(ds)G_(ds)T_(ds)G_(ks)G_(ks) ^(m)C_(k) 1200799 2567 2582 123592 123607ATATTAGAGTATGTGGA_(ks)T_(ks)A_(ks)T_(ds)T_(ds)A_(ys)G_(ds)A_(ds)G_(ds)T_(ds) 27 2813A_(ds)T_(ds)G_(ds)T_(ks)G_(ks)G_(k) 1200800 2568 2583 123593 123608TATATUAGAGTATGTGT_(ks)A_(ks)T_(ks)A_(ds)T_(ds)U_(ys)A_(ds)G_(ds)A_(ds)G_(ds) 61 2911T_(ds)A_(ds)T_(ds)G_(ks)T_(ks)G_(k) 1200801 2570 2585 123595 123610TCTATATTAGAGTATG T_(ks)^(m)C_(ks)T_(ks)A_(ds)T_(ds)A_(ys)T_(ds)T_(ds)A_(ds)G_(ds) 77 887A_(ds)G_(ds)T_(ds)A_(ks)T_(ks)G_(k)

TABLE 52Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ    ID ID SEQ ID SEQ ID YAP1 NO: 1 NO: 1 NO: 2 NO: 2 SEQ SEQCompound Start Stop Start Stop YAP1 ID Number Site Site Site SiteSequence (5' to 3') CHEMSITRY NOTATION (% UT) NO 715487 3630 3645 124655124670 ATTACTTCATAGCTTA A_(ks)T_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 29 52 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k)958499 2565 2580 123590 123605 ATTAGAGTATGTGGCAA_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 14 810G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1074461 2529 2544 123554 123569GAAATTGTCTCATGCC G_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m) 15 2800 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(k) 1200788 2529 2544 123554 123569 GAAATUGTCTCATGCCG_(ks)A_(ks)A_(ks)A_(ds)T_(ds)U_(ys)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)19 2912 C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(k) 1200789 2530 2545123555 123570 GGAAAUTGTCTCATGCG_(ks)G_(ks)A_(ks)A_(ds)A_(ds)U_(ys)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 122913 T_(ds) ^(m)C_(ds)A_(ds)T_(ks)G_(ks) ^(m)C_(k) 1200790 2531 2546123556 123571 TGGAAATTGTCTCATGT_(ks)G_(ks)G_(ks)A_(ds)A_(ds)A_(ys)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 332807 C_(ds)T_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(k) 1200791 2532 2547 123557123572 ATGGAAATTGTCTCATA_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ys)A_(ds)T_(ds)T_(ds)G_(ds) 46 2808T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)A_(ks)T_(k) 1200792 2534 2549 123559123574 ATATGGAAATTGTCTCA_(ks)T_(ks)A_(ks)T_(ds)G_(ds)G_(ys)A_(ds)A_(ds)A_(ds)T_(ds) 52 656T_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 1200802 4436 4451 125461125476 TATAACTGGGCAAATTT_(ks)A_(ks)T_(ks)A_(ds)A_(ds)C_(ys)T_(ds)G_(ds)G_(ds)G_(ds) ^(m) 892815 C_(ds)A_(ds)A_(ds)A_(ks)T_(k) 1200803 4438 4453 125463 125478GGTATAACTGGGCAAA G_(ks)G_(ks)T_(ks)A_(ds)T_(ds)A_(ys)A_(ds)^(m)C_(ds)T_(ds)G_(ds) 22 1427 G_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)A_(k)1200804 4439 4454 125464 125479 AGGTAUAACTGGGCAAA_(ks)G_(ks)G_(ks)T_(ds)A_(ds)U_(ys)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) 442914 G_(ds)G_(ds)G_(ds) ^(m)C_(ks)A_(ks)A_(k) 1200805 4440 4455 125465125480 GAGGTATAACTGGGCAG_(ks)A_(ks)G_(ks)G_(ds)T_(ds)A_(ys)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) 501503 T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1200806 4441 4456 125466125481 TGAGGUATAACTGGGCT_(ks)G_(ks)A_(ks)G_(ds)G_(ds)U_(ys)A_(ds)T_(ds)A_(ds)A_(ds) ^(m) 242915 C_(ds)T_(ds)G_(ds)G_(ks)G_(ks) ^(m)C_(k) 1200807 4442 4457 125467125482 CTGAGGTATAACTGGG^(m)C_(ks)T_(ks)G_(ks)A_(ds)G_(ds)G_(ys)T_(ds)A_(ds)T_(ds) 69 2801A_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ks)G_(ks)G_(k) 1200808 4443 4458 125468125483 ACTGAGGTATAACTGG A_(ks)^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ys)G_(ds)T_(ds)A_(ds)T_(ds) 45 392A_(ds)A_(ds) ^(m)C_(ds)T_(ks)G_(ks)G_(k) 1200809 4444 4459 125469 125484CACTGAGGTATAACTG ^(m)C_(ks)A_(ks)^(m)C_(ks)T_(ds)G_(ds)A_(ys)G_(ds)G_(ds)T_(ds) 69 2802A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ks)T_(ks)G_(k) 1200810 4446 4461 125471125486 AACACUGAGGTATAAC A_(ks)A_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)U_(ys)G_(ds)A_(ds)G_(ds) 94 2916G_(ds)T_(ds)A_(ds)T_(ds)A_(ks)A_(ks) ^(m)C_(k) 1200811 4595 4610 125620125635 TTACAUTAGGAACAAG T_(ks)T_(ks)A_(ks)^(m)C_(ds)A_(ds)U_(ys)T_(ds)A_(ds)G_(ds)G_(ds) 62 2917 A_(ds)A_(ds)^(m)C_(ds)A_(ks)A_(ks)G_(k) 1200812 4597 4612 125622 125637TTTTACATTAGGAACAT_(ks)T_(ks)T_(ks)T_(ds)A_(ds)C_(ys)A_(ds)T_(ds)T_(ds)A_(ds) 59 2928G_(ds)G_(ds)A_(ds)A_(ks) ^(m)C_(ks)A_(k) 1200813 4598 4613 125623 125638CTTTTACATTAGGAAC ^(m)C_(ks)T_(ks)T_(ks)T_(ds)T_(ds)A_(ys)^(m)C_(ds)A_(ds)T_(ds) 58 1124 T_(ds)A_(ds)G_(ds)G_(ds)A_(ks)A_(ks)^(m)C_(k) 1200814 4599 4614 125624 125639 ACTTTUACATTAGGAA A_(ks)^(m)C_(ks)T_(ks)T_(ds)T_(ds)U_(ys)A_(ds) ^(m)C_(ds)A_(ds) 73 2918T_(ds)T_(ds)A_(ds)G_(ds)G_(ks)A_(ks)A_(k) 1200815 4600 4615 125625125640 CACTTUTACATTAGGA ^(m)C_(ks)A_(ks)^(m)C_(ks)T_(ds)T_(ds)U_(ys)T_(ds)A_(ds) ^(m)C_(ds) 55 2919A_(ds)T_(ds)T_(ds)A_(ds)G_(ks)G_(ks)A_(k) 1200816 4601 4616 125626125641 GCACTUTTACATTAGG G_(ks) ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)U_(ys)T_(ds)T_(ds)A_(ds) ^(m) 37 2920C_(ds)A_(ds)T_(ds)T_(ds)A_(ks)G_(ks)G_(k) 1200817 4602 4617 125627125642 AGCACUTTTACATTAG A_(ks)G_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)U_(ys)T_(ds)T_(ds)T_(ds) 38 2921 A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ks)A_(ks)G_(k) 1200818 4603 4618 125628 125643AAGCACTTTTACATTA A_(ks)A_(ks)G_(ks)^(m)C_(ds)A_(ds)C_(ys)T_(ds)T_(ds)T_(ds)T_(ds) 31 2821 A_(ds)^(m)C_(ds)A_(ds)T_(ks)T_(ks)A_(k) 1200819 4605 4620 125630 125645TTAAGCACTTTTACAT T_(ks)T_(ks)A_(ks)A_(ds)G_(ds)C_(ys)A_(ds)^(m)C_(ds)T_(ds)T_(ds) 101 2822 T_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ks)T_(k)1200820 4795 4810 125820 125835 GGAAGATCTGAAACTCG_(ks)G_(ks)A_(ks)A_(ds)G_(ds)A_(ys)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) 242823 A_(ds)A_(ds)A_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 1200821 4797 4812125822 125837 TTGGAAGATCTGAAACT_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ys)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 592824 T_(ds)G_(ds)A_(ds)A_(ks)A_(ks) ^(m)C_(k) 1200822 4798 4813 125823125838 TTTGGAAGATCTGAAAT_(ks)T_(ks)T_(ks)G_(ds)G_(ds)A_(ys)A_(ds)G_(ds)A_(ds)T_(ds) ^(m) 552938 C_(ds)T_(ds)G_(ds)A_(ks)A_(ks)A_(k) 1200823 4799 4814 125824 125839CTTTGGAAGATCTGAA^(m)C_(ks)T_(ks)T_(ks)T_(ds)G_(ds)G_(ys)A_(ds)A_(ds)G_(ds) 46 2826A_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ks)A_(ks)A_(k) 1200824 4800 4815 125825125840 GCTTTGGAAGATCTGA G_(ks)^(m)C_(ks)T_(ks)T_(ds)T_(ds)G_(ys)G_(ds)A_(ds)A_(ds)G_(ds) 43 2044A_(ds)T_(ds) ^(m)C_(ds)T_(ks)G_(ks)A_(k) 1200825 4801 4816 125826 125841TGCTTUGGAAGATCTG T_(ks)G_(ks)^(m)C_(ks)T_(ds)T_(ds)U_(ys)G_(ds)G_(ds)A_(ds)A_(ds) 39 2922G_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(k) 1200826 4802 4817 125827 125842GTGCTUTGGAAGATCT G_(ks)T_(ks)G_(ks)^(m)C_(ds)T_(ds)U_(ys)T_(ds)G_(ds)G_(ds)A_(ds) 26 2923A_(ds)G_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(k) 1200827 4803 4818 125828 125843AGTGCUTTGGAAGATC A_(ks)G_(ks)T_(ks)G_(ds)^(m)C_(ds)U_(ys)T_(ds)T_(ds)G_(ds)G_(ds) 67 2924A_(ds)A_(ds)G_(ds)A_(ks)T_(ks) ^(m)C_(k) 1200828 4805 4820 125830 125845ATAGTGCTTTGGAAGA A_(ks)T_(ks)A_(ks)G_(ds)T_(ds)G_(ys)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 54 2829 G_(ds)G_(ds)A_(ds)A_(ks)G_(ks)A_(k)1200829 N/A N/A 94729 94744 AGGATGCATGGTTTTTA_(ks)G_(ks)G_(ks)A_(ds)T_(ds)G_(ys) ^(m)C_(ds)A_(ds)T_(ds)G_(ds) 492830 G_(ds)T_(ds)T_(ds)T_(ks)T_(ks)T_(k) 1200830 N/A N/A 94731 94746TTAGGATGCATGGTTT T_(ks)T_(ks)A_(ks)G_(ds)G_(ds)A_(ys)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 50 2831 T_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1200831 N/AN/A 94732 94747 TTTAGGATGCATGGTTT_(ks)T_(ks)T_(ks)A_(ds)G_(ds)G_(ys)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 422832 A_(ds)T_(ds)G_(ds)G_(ks)T_(ks)T_(k) 1200832 N/A N/A 94733 94748ATTTAGGATGCATGGTA_(ks)T_(ks)T_(ks)T_(ds)A_(ds)G_(ys)G_(ds)A_(ds)T_(ds)G_(ds) ^(m) 612833 C_(ds)A_(ds)T_(ds)G_(ks)G_(ks)T_(k) 1200833 N/A N/A 94734 94749GATTTAGGATGCATGGG_(ks)A_(ks)T_(ks)T_(ds)T_(ds)A_(ys)G_(ds)G_(ds)A_(ds)T_(ds) 31 2834G_(ds) ^(m)C_(ds)A_(ds)T_(ks)G_(ks)G_(k) 1200834 N/A N/A 94735 94750AGATTUAGGATGCATGA_(ks)G_(ks)A_(ks)T_(ds)T_(ds)U_(ys)A_(ds)G_(ds)G_(ds)A_(ds) 37 2925T_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(k) 1200835 N/A N/A 94736 94751CAGATUTAGGATGCAT^(m)C_(ks)A_(ks)G_(ks)A_(ds)T_(ds)U_(ys)T_(ds)A_(ds)G_(ds) 82 2926G_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(ks)T_(k) 1200836 N/A N/A 9473794752 TCAGAUTTAGGATGCA T_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ds)U_(ys)T_(ds)T_(ds)A_(ds)G_(ds) 72 2927G_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(k) 1200837 N/A N/A 94739 94754ATTCAGATTTAGGATG A_(ks)T_(ks)T_(ks)^(m)C_(ds)A_(ds)G_(ys)A_(ds)T_(ds)T_(ds)T_(ds) 82 2838A_(ds)G_(ds)G_(ds)A_(ks)T_(ks)G_(k) 1200838 N/A N/A 115903 115918ATATGGTTTTGTGTGTA_(ks)T_(ks)A_(ks)T_(ds)G_(ds)G_(ys)T_(ds)T_(ds)T_(ds)T_(ds) 65 2839G_(ds)T_(ds)G_(ds)T_(ks)G_(ks)T_(k) 1200839 N/A N/A 115905 115920TTATAUGGTTTTGTGTT_(ks)T_(ks)A_(ks)T_(ds)A_(ds)U_(ys)G_(ds)G_(ds)T_(ds)T_(ds) 44 2928T_(ds)T_(ds)G_(ds)T_(ks)G_(ks)T_(k) 1200840 N/A N/A 115906 115921CTTATATGGTTTTGTG^(m)C_(ks)T_(ks)T_(ks)A_(ds)T_(ds)A_(ys)T_(ds)G_(ds)G_(ds)T_(ds) 48 2788T_(ds)T_(ds)T_(ds)G_(ks)T_(ks)G_(k) 1200841 N/A N/A 115907 115922TCTTAUATGGTTTTGT T_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ds)U_(ys)A_(ds)T_(ds)G_(ds)G_(ds) 76 2929T_(ds)T_(ds)T_(ds)T_(ks)G_(ks)T_(k) 1200842 N/A N/A 115908 115923CTCTTATATGGTTTTG ^(m)C_(ks)T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ys)T_(ds)A_(ds)T_(ds) 168 2842G_(ds)G_(ds)T_(ds)T_(ds)T_(ks)T_(ks)G_(k) 1200843 N/A N/A 115909 115924ACTCTUATATGGTTTT A_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)U_(ys)A_(ds)T_(ds)A_(ds) 46 2930T_(ds)G_(ds)G_(ds)T_(ds)T_(ks)T_(ks)T_(k) 1200844 N/A N/A 115910 115925AACTCUTATATGGTTT A_(ks)A_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)U_(ys)T_(ds)A_(ds)T_(ds) 132 2931A_(ds)T_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1200845 N/A N/A 115911 115926CAACTCTTATATGGTT ^(m)C_(ks)A_(ks)A_(ks)^(m)C_(ds)T_(ds)C_(ys)T_(ds)T_(ds)A_(ds) 100 2861T_(ds)A_(ds)T_(ds)G_(ds)G_(ks)T_(ks)T_(k) 1200846 N/A N/A 115913 115928GACAACTCTTATATGG G_(ks)A_(ks) ^(m)C_(ks)A_(ds)A_(ds)C_(ys)T_(ds)^(m)C_(ds)T_(ds) 38 2862 T_(ds)A_(ds)T_(ds)A_(ds)T_(ks)G_(ks)G_(k)1200847 N/A N/A 117325 117340 ATTGCAATCTGTCTGA A_(ks)T_(ks)T_(ks)G_(ds)^(m)C_(ds)A_(ys)A_(ds)T_(ds) ^(m)C_(ds) 54 2843 T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ks)G_(ks)A_(k) 1200848 N/A N/A 117327 117342ATATTGCAATCTGTCT A_(ks)T_(ks)A_(ks)T_(ds)T_(ds)G_(ys)^(m)C_(ds)A_(ds)A_(ds)T_(ds) ^(m) 58 2844 C_(ds)T_(ds)G_(ds)T_(ks)^(m)C_(ks)T_(k) 1200849 N/A N/A 117328 117343 AATATUGCAATCTGTCA_(ks)A_(ks)T_(ks)A_(ds)T_(ds)U_(ys)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) 532932 T_(ds) ^(m)C_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 1200850 N/A N/A117329 117344 TAATAUTGCAATCTGTT_(ks)A_(ks)A_(ks)T_(ds)A_(ds)U_(ys)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 832933 A_(ds)T_(ds) ^(m)C_(ds)T_(ks)G_(ks)T_(k) 1200851 N/A N/A 117330117345 GTAATATTGCAATCTGG_(ks)T_(ks)A_(ks)A_(ds)T_(ds)A_(ys)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 251404 A_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(k) 1200852 N/A N/A 117331117346 TGTAAUATTGCAATCTT_(ks)G_(ks)T_(ks)A_(ds)A_(ds)U_(ys)A_(ds)T_(ds)T_(ds)G_(ds) ^(m) 322934 C_(ds)A_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(k) 1200853 N/A N/A 117332117347 ATGTAATATTGCAATCA_(ks)T_(ks)G_(ks)T_(ds)A_(ds)A_(ys)T_(ds)A_(ds)T_(ds)T_(ds) 69 2848G_(ds) ^(m)C_(ds)A_(ds)A_(ks)T_(ks) ^(m)C_(k) 1200854 N/A N/A 117333117348 TATGTAATATTGCAATT_(ks)A_(ks)T_(ks)G_(ds)T_(ds)A_(ys)A_(ds)T_(ds)A_(ds)T_(ds) 91 2849T_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(k) 1200855 N/A N/A 117335 117350TTTATGTAATATTGCAT_(ks)T_(ks)T_(ks)A_(ds)T_(ds)G_(ys)T_(ds)A_(ds)A_(ds)T_(ds) 56 2850A_(ds)T_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(k) 1200856 N/A N/A 117755 117770TGTATGTCAGAAGAGT T_(ks)G_(ks)T_(ks)A_(ds)T_(ds)G_(ys)T_(ds)^(m)C_(ds)A_(ds)G_(ds) 29 2863 A_(ds)A_(ds)G_(ds)A_(ks)G_(ks)T_(k)1200857 N/A N/A 117757 117772 AGTGTATGTCAGAAGAA_(ks)G_(ks)T_(ks)G_(ds)T_(ds)A_(ys)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 4 2864A_(ds)G_(ds)A_(ds)A_(ks)G_(ks)A_(k) 1200858 N/A N/A 117758 117773AAGTGUATGTCAGAAGA_(ks)A_(ks)G_(ks)T_(ds)G_(ds)U_(ys)A_(ds)T_(ds)G_(ds)T_(ds) ^(m) 102935 C_(ds)A_(ds)G_(ds)A_(ks)A_(ks)G_(k) 1200859 N/A N/A 117759 117774AAAGTGTATGTCAGAAA_(ks)A_(ks)A_(ks)G_(ds)T_(ds)G_(ys)T_(ds)A_(ds)T_(ds)G_(ds) 28 2866T_(ds) ^(m)C_(ds)A_(ds)G_(ks)A_(ks)A_(k) 1200860 N/A N/A 117760 117775TAAAGUGTATGTCAGAT_(ks)A_(ks)A_(ks)A_(ds)G_(ds)U_(ys)G_(ds)T_(ds)A_(ds)T_(ds) 16 2936G_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(k) 1200861 N/A N/A 117761 117776TTAAAGTGTATGTCAGT_(ks)T_(ks)A_(ks)A_(ds)A_(ds)G_(ys)T_(ds)G_(ds)T_(ds)A_(ds) 10 2868T_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(k) 1200862 N/A N/A 117762 117777TTTAAAGTGTATGTCAT_(ks)T_(ks)T_(ks)A_(ds)A_(ds)A_(ys)G_(ds)T_(ds)G_(ds)T_(ds) 17 2869A_(ds)T_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1200863 N/A N/A 117763 117778CTTTAAAGTGTATGTC^(m)C_(ks)T_(ks)T_(ks)T_(ds)A_(ds)A_(ys)A_(ds)G_(ds)T_(ds) 41 1634G_(ds)T_(ds)A_(ds)T_(ds)G_(ks)T_(ks) ^(m)C_(k) 1200864 N/A N/A 117765117780 AACTTUAAAGTGTATG A_(ks)A_(ks)^(m)C_(ks)T_(ds)T_(ds)U_(ys)A_(ds)A_(ds)A_(ds)G_(ds) 84 2937T_(ds)G_(ds)T_(ds)A_(ks)T_(ks)G_(k) 1200865 N/A N/A 119667 119682TAAGGUTTCCCAGATT T_(ks)A_(ks)A_(ks)G_(ds)G_(ds)U_(ys)T_(ds)T_(ds)^(m)C_(ds) ^(m) 54 2938 C_(ds) ^(m)C_(ds)A_(ds)G_(ds)A_(ks)T_(ks)T_(k)1200866 N/A N/A 119669 119684 AGTAAGGTTTCCCAGAA_(ks)G_(ks)T_(ks)A_(ds)A_(ds)G_(ys)G_(ds)T_(ds)T_(ds)T_(ds) ^(m) 412852 C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(k) 1200867 N/A N/A119670 119685 AAGTAAGGTTTCCCAGA_(ks)A_(ks)G_(ks)T_(ds)A_(ds)A_(ys)G_(ds)G_(ds)T_(ds)T_(ds) 38 2853T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(k) 1200868 N/A N/A119671 119686 TAAGTAAGGTTTCCCAT_(ks)A_(ks)A_(ks)G_(ds)T_(ds)A_(ys)A_(ds)G_(ds)G_(ds)T_(ds) 36 2854T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 1200869 N/A N/A119672 119687 CTAAGUAAGGTTTCCC^(m)C_(ks)T_(ks)A_(ks)A_(ds)G_(ds)U_(ys)A_(ds)A_(ds)G_(ds) 25 2939G_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(k) 1200870 N/A N/A119673 119688 ACTAAGTAAGGTTTCC A_(ks)^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ys)T_(ds)A_(ds)A_(ds)G_(ds) 73 2855G_(ds)T_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 1200871 N/A N/A 119674119689 GACTAAGTAAGGTTTC G_(ks)A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ys)G_(ds)T_(ds)A_(ds)A_(ds) 65 2856G_(ds)G_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(k) 1200872 N/A N/A 119675 119690AGACTAAGTAAGGTTT A_(ks)G_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ys)A_(ds)G_(ds)T_(ds)A_(ds) 98 2857A_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1200873 N/A N/A 119677 119692TTAGACTAAGTAAGGTT_(ks)T_(ks)A_(ks)G_(ds)A_(ds)C_(ys)T_(ds)A_(ds)A_(ds)G_(ds) 55 2858T_(ds)A_(ds)A_(ds)G_(ks)G_(ks)T_(k)

Example 6 Dose-Dependent Inhibition of Human Yap1 in A-431 Cells by cEtGapmers

Modified oligonucleotides described in the studies above were tested atvarious doses in A-431 cells. Cultured A-431 cells at a density of 5,000cells per well were treated using free uptake with modifiedoligonucleotides diluted to concentrations described in the tablesbelow. After approximately 48 hours, Yap1 mRNA levels were measured aspreviously described using the Human Yap1 primer-probe set RTS4814. Yap1mRNA levels were normalized to total RNA content, as measured byRIBOGREEN®. Results are presented in the tables below as percent controlof the amount of Yap1 mRNA relative to untreated control cells (% UTC).IC50s were calculated using a linear regression on a log/linear plot ofthe data in excel.

TABLE 53 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 148 nM 444nM 1333 nM 4000 nM (μM) 715415 84 59 55 42 1.8 715423 83 91 80 57 >4.0715433 87 72 65 40 2.5 715434 84 69 64 43 2.8 715473 89 67 50 30 1.3715478 70 47 29 16 0.4 715479 98 80 77 64 >4.0 715480 91 79 67 59 >4.0715483 82 58 43 35 1.1 715486 93 89 81 56 >4.0 715487 87 56 48 29 1.0715490 98 89 76 43 4.1 715500 97 72 67 48 3.6 715501 82 82 68 56 >4.0715508 78 70 67 43 3.5 715510 88 67 59 45 2.4 715523 100 62 75 44 3.2715555 93 71 63 42 2.5 715577 87 76 73 45 >4.0

TABLE 54 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 148 nM 444nM 1333 nM 4000 nM (μM) 715414 91 91 102 67 >4.0 715435 80 67 61 48 3.4715471 82 103 105 79 >4.0 715478 72 59 31 18 0.6 715558 94 112 8066 >4.0 715582 98 63 93 70 >4.0 716370 81 79 69 49 >4.0 716376 103 94 7950 >4.0 716424 76 69 51 44 2.0 716445 89 82 56 44 2.6 716454 91 71 54 482.6 716469 71 78 89 39 >4.0 716481 89 90 58 32 2.0 716484 88 78 8055 >4.0 716493 95 97 86 72 >4.0 716496 74 87 64 49 >4.0 716502 73 57 4530 0.8 716505 83 103 82 66 >4.0 716577 109 93 79 60 >4.0

TABLE 55 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 148 nM 444nM 1333 nM 4000 nM (μM) 715478 76 56 32 18 0.6 716381 106 90 80 44 4.2716387 94 94 80 67 >4.0 716407 84 75 72 39 3.0 716419 89 84 49 47 2.5716438 93 75 62 49 3.4 716455 95 70 49 25 1.2 716479 88 78 55 57 >4.0716480 80 56 38 39 1.0 716489 84 83 69 61 >4.0 716500 88 96 79 46 >4.0716501 91 69 66 55 >4.0 716503 91 80 67 64 >4.0 716513 82 73 39 39 1.4716524 103 92 96 62 >4.0 716537 120 96 88 63 >4.0 716543 62 99 7964 >4.0 716548 99 89 79 67 >4.0 716554 87 90 76 50 >4.0

Example 7 Dose-Dependent Inhibition of Human Yap1 in A-431 Cells by cEtGapmers

Modified oligonucleotides described in the studies above were tested atvarious doses in A-431 cells. Cultured A-431 cells at a density of10,000 cells per well were treated using free uptake with modifiedoligonucleotides diluted to concentrations described in the tablesbelow. After approximately 48 hours, Yap1 mRNA levels were measured aspreviously described using the Human Yap1 primer-probe set RTS36584.Yap1 mRNA levels were normalized to total RNA content, as measured byRIBOGREEN®. Results are presented in the tables below as percent controlof the amount of Yap1 mRNA relative to untreated control cells (% UTC).IC50s were calculated using a linear regression on a log/linear plot ofthe data in excel.

TABLE 56 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 15.6 nM 62.5nM 250.0 nM 4000.00 nM (μM) 715483 78 38 15 6 0.05 715491 92 83 48 280.27 958356 84 79 39 21 0.18 958361 100 80 42 22 0.22 958369 107 68 3417 0.17 958370 98 74 41 22 0.20 958371 89 57 27 11 0.10 958373 72 45 2117 0.05 958375 74 35 11 5 0.04 958377 90 60 38 17 0.13 958403 94 63 3012 0.12 958476 71 30 13 6 0.03 958496 86 53 27 9 0.09 958536 94 67 30 160.14 958596 69 38 14 7 0.04 958721 72 32 9 3 0.03 958726 99 70 40 160.17 958736 83 38 14 7 0.06 958796 91 62 32 15 0.13

TABLE 57 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 15.6 nM 62.5nM 250.0 nM 4000.00 nM (μM) 715483 79 45 15 4 0.1 958451 98 74 51 23 0.2958466 84 81 49 30 0.3 958481 86 62 28 14 0.1 958486 87 73 45 22 0.2958491 94 65 27 10 0.1 958506 80 55 24 10 0.1 958526 118 83 40 17 0.2958531 92 63 26 13 0.1 958541 81 51 18 9 0.1 958546 91 72 45 22 0.2958551 95 73 34 14 0.2 958556 103 95 63 34 0.5 958616 78 49 29 17 0.1958686 75 69 38 18 0.1 958731 85 64 39 19 0.1 958761 84 73 41 24 0.2958781 77 45 20 10 0.1 958786 106 84 51 25 0.3

TABLE 58 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 15.6 nM 62.5nM 250.0 nM 4000.00 nM (μM) 715483 84 44 15 5 0.1 958457 91 50 24 13 0.1958472 92 63 39 23 0.2 958477 83 37 14 6 0.1 958497 82 35 11 3 0.1958527 89 74 35 13 0.1 958532 88 44 16 7 0.1 958537 100 56 21 11 0.1958542 90 70 35 17 0.1 958547 98 74 43 22 0.2 958567 99 80 44 16 0.2958577 81 51 22 11 0.1 958587 94 49 18 7 0.1 958622 79 50 18 7 0.1958727 90 42 25 8 0.1 958742 105 70 39 20 0.2 958752 102 66 26 9 0.1958757 110 89 43 27 0.3 958807 92 65 30 10 0.1

TABLE 59 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 15.6 nM 62.5nM 250.0 nM 4000.00 nM (μM) 715483 83 44 16 4 0.1 958498 70 21 5 2 0.02958507 93 69 38 19 0.2 958518 95 55 18 4 0.1 958533 99 61 27 12 0.1958553 68 23 12 5 0.03 958562 105 95 59 28 0.4 958563 94 54 22 10 0.1958572 83 77 31 22 0.2 958573 81 56 23 8 0.1 958597 104 46 45 20 0.2958603 70 27 11 4 0.03 958623 100 62 29 10 0.1 958668 81 38 12 5 0.1958737 104 92 57 29 0.4 958758 83 66 33 12 0.1 958763 98 60 22 8 0.1958767 101 57 20 10 0.1 958798 101 61 26 12 0.1

TABLE 60 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 15.6 nM 62.5nM 250.0 nM 4000.00 nM (μM) 715483 79 40 13 3 0.1 958473 85 60 29 17 0.1958508 65 64 32 13 0.1 958523 86 64 31 12 0.1 958538 101 77 52 30 0.3958543 84 63 36 18 0.1 958554 70 34 11 4 0.03 958558 84 83 67 35 0.5958568 88 65 37 21 0.1 958578 78 52 23 10 0.1 958588 93 73 46 27 0.2958593 99 60 27 15 0.1 958598 93 58 36 19 0.1 958648 80 65 48 24 0.2958658 90 88 59 29 0.4 958718 104 80 44 24 0.2 958753 72 48 20 11 0.1958793 88 61 42 25 0.2 958813 81 79 47 29 0.2

TABLE 61 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 15.6 nM 62.5nM 250.0 nM 4000.00 nM (μM) 715483 80 38 13 4 0.1 958454 72 40 12 4 0.04958474 63 37 18 11 0.03 958484 77 38 10 4 0.05 958499 54 12 3 1 <0.01958509 66 37 15 7 0.03 958529 103 64 27 11 0.1 958534 85 48 21 9 0.1958569 82 49 24 7 0.1 958579 85 52 24 12 0.1 958589 75 50 19 8 0.1958599 100 74 44 16 0.2 958614 84 49 22 13 0.1 958644 97 85 50 24 0.3958659 91 68 28 9 0.1 958724 89 55 20 6 0.1 958729 73 44 13 4 0.05958739 77 46 19 7 0.1 958799 88 53 25 10 0.1

TABLE 62 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 15.6 nM 62.5nM 250.0 nM 4000.00 nM (μM) 715483 88 40 12 4 0.1 958485 68 38 13 8 0.04958525 94 57 26 8 0.1 958544 65 77 40 17 0.1 958545 75 50 19 8 0.1958549 98 78 47 28 0.3 958550 91 60 26 10 0.1 958555 99 73 34 13 0.2958565 83 62 30 13 0.1 958580 95 59 24 9 0.1 958590 71 33 9 4 0.03958594 91 70 42 20 0.2 958615 91 60 34 18 0.1 958650 82 51 17 7 0.1958725 65 36 7 1 0.03 958730 88 48 19 7 0.1 958734 87 65 35 15 0.1958785 78 52 18 6 0.1 958819 79 63 34 19 0.1

TABLE 63 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 15.6 nM 62.5nM 250.0 nM 4000.00 nM (μM) 715483 87 45 15 4 0.1 715483 77 36 10 3 0.04715487 77 44 13 4 0.1 716454 84 39 12 6 0.1 958490 81 54 26 13 0.1958500 91 63 32 16 0.1 958505 81 72 53 21 0.2 958535 98 64 38 19 0.2958540 62 28 14 8 0.02 958570 93 60 33 17 0.1 958575 89 58 34 20 0.1958585 95 71 40 17 0.2 958595 83 57 37 16 0.1 958600 69 44 23 14 0.05958605 76 63 34 9 0.1 958625 86 59 35 17 0.1 958735 116 69 37 23 0.2958795 90 69 38 20 0.2 958805 90 89 56 28 0.3

Example 8 Dose-Dependent Inhibition of Human Yap1 in A-431 Cells by cEtGapmers

Modified oligonucleotides described in the studies above were tested atvarious doses in A-431 cells. Cultured A-431 cells at a density of10,000 cells per well were treated using free uptake with modifiedoligonucleotides diluted to concentrations described in the tablesbelow. After approximately 48 hours, Yap1 mRNA levels were measured aspreviously described using the Human Yap1 primer-probe set RTS4814. Yap1mRNA levels were normalized to total RNA content, as measured byRIBOGREEN®. Results are presented in the tables below as percent controlof the amount of Yap1 mRNA relative to untreated control cells (% UTC).IC50s were calculated using a linear regression on a log/linear plot ofthe data in excel.

TABLE 64 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 27 4 3 2 <0.02 1074368 67 34 1510 0.1 1074464 25 6 3 3 <0.02 1074560 50 16 6 4 <0.02 1074753 42 10 6 4<0.02 1075137 70 22 8 4 0.1 1075233 45 12 5 3 <0.02 1075712 69 38 13 70.1 1075744 55 22 9 7 <0.02 1075808 38 9 4 4 <0.02 1075968 74 37 11 50.1 1076000 71 31 10 5 0.1 1076064 68 26 10 5 0.1 1076256 68 33 11 6 0.11076288 31 7 3 4 <0.02 1076416 67 33 13 7 0.1 1076448 61 19 4 3 <0.021076449 44 8 3 2 <0.02 1076481 21 4 2 3 <0.02

TABLE 65 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 24 4 2 2 <0.02 1074274 42 14 75 <0.02 1074593 50 20 9 8 <0.02 1074594 53 23 10 5 <0.02 1074595 67 21 84 0.04 1074626 54 18 8 5 <0.02 1074627 17 5 3 3 <0.02 1074755 28 9 5 3<0.02 1074817 50 22 13 11 <0.02 1074850 63 20 7 5 0.04 1075041 62 31 117 0.05 1075138 66 27 8 5 0.05 1075457 52 21 8 6 <0.02 1075458 74 43 17 60.1 1075778 56 29 10 5 0.03 1075810 67 28 12 7 0.1 1075842 27 7 3 3<0.02 1076067 45 13 5 4 <0.02 1076386 61 30 11 5 0.04

TABLE 66 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 28 4 2 2 <0.02 1074563 80 31 75 0.1 1074564 40 14 7 4 <0.02 1074628 29 13 7 6 <0.02 1074723 56 24 11 8<0.02 1074756 22 7 4 4 <0.02 1074851 51 19 9 7 <0.02 1074852 36 11 4 4<0.02 1075395 60 18 7 5 <0.02 1075748 81 36 12 7 0.1 1075876 47 20 7 5<0.02 1075939 46 19 10 8 <0.02 1076003 60 28 17 11 0.04 1076004 27 7 3 2<0.02 1076260 61 30 12 5 0.05 1076291 75 26 8 5 0.1 1076323 41 35 13 5<0.02 1076388 87 40 13 6 0.1 1076483 63 27 11 6 0.04

TABLE 67 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 23 4 2 2 <0.02 1074245 47 21 85 <0.02 1074565 47 20 9 6 <0.02 1074566 41 12 5 3 <0.02 1074597 35 15 87 <0.02 1074629 21 5 3 3 <0.02 1074630 57 23 10 6 <0.02 1074726 26 8 4 3<0.02 1074758 74 23 8 5 0.1 1075078 65 32 12 4 0.1 1075749 46 22 7 4<0.02 1075781 52 15 4 3 <0.02 1075813 57 31 11 5 0.04 1076293 49 18 6 5<0.02 1076326 53 20 6 3 <0.02 1076453 11 2 1 2 <0.02 1076486 84 45 16 60.1 1076516 64 39 18 13 0.1 1076549 53 24 10 6 <0.02

TABLE 68 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 31 5 2 2 <0.02 1074407 55 27 138 <0.02 1074535 57 21 7 5 <0.02 1074536 64 24 9 6 0.04 1074728 28 7 4 4<0.02 1074792 48 17 7 5 <0.02 1075047 80 63 27 10 0.2 1075048 76 42 13 50.1 1075111 42 11 6 5 <0.02 1075112 87 36 13 7 0.1 1075143 59 21 5 3<0.02 1075207 82 51 17 7 0.1 1075686 72 44 18 14 0.1 1075784 54 18 5 3<0.02 1076070 55 17 8 6 <0.02 1076294 76 50 21 11 0.1 1076295 55 17 5 3<0.02 1076327 73 38 17 9 0.1 1076456 43 14 5 3 <0.02

TABLE 69 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 36 5 2 2 <0.02 1074250 67 35 159 0.1 1074313 56 21 9 5 <0.02 1074409 60 30 13 7 0.04 1074537 47 21 6 4<0.02 1074762 74 32 14 8 0.1 1074794 56 23 10 6 <0.02 1075081 76 50 22 90.1 1075401 62 26 11 7 0.04 1075465 75 35 14 9 0.1 1075689 97 59 19 80.2 1075785 29 7 3 3 <0.02 1075816 66 29 12 8 0.1 1076330 57 31 9 4 0.041076393 54 20 8 5 <0.02 1076458 88 52 23 10 0.2 1076489 43 13 4 3 <0.021076490 36 9 4 3 <0.02 1076552 73 40 17 12 0.1

TABLE 70 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 27 4 2 2 <0.02 1074251 73 33 1610 0.1 1074315 57 26 9 5 0.03 1074411 47 20 8 6 <0.02 1074443 69 35 14 80.1 1074795 38 14 7 5 <0.02 1075115 57 41 17 9 0.1 1075146 67 38 16 80.1 1075242 71 39 18 12 0.1 1075243 50 18 7 5 <0.02 1075498 82 40 21 160.1 1075819 48 18 7 5 <0.02 1076298 92 58 29 18 0.2 1076299 68 38 13 50.1 1076426 68 46 24 18 0.1 1076427 75 30 9 4 0.1 1076459 67 32 13 7 0.11076491 81 45 21 10 0.1 1076523 67 38 18 7 0.1

TABLE 71 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 29 5 2 2 <0.02 1074221 75 38 147 0.1 1074413 50 19 6 3 <0.02 1074444 49 21 7 4 <0.02 1074508 62 30 14 80.05 1074509 44 12 6 5 <0.02 1075052 40 10 4 4 <0.02 1075053 61 24 8 50.04 1075084 103 72 37 14 0.3 1075757 43 14 5 2 <0.02 1075916 73 34 14 80.1 1076077 53 19 9 5 <0.02 1076396 64 22 5 3 0.04 1076397 43 14 5 4<0.02 1076460 79 53 25 12 0.2 1076461 65 24 7 3 0.04 1076524 71 30 12 70.1 1076525 43 14 5 2 <0.02 1076556 72 46 19 11 0.1

TABLE 72 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 95 89 82 81 >2.0 1074222 59 218 5 <0.02 1074318 48 12 6 4 <0.02 1074414 64 34 14 7 0.1 1074445 57 19 86 <0.02 1074446 39 11 5 3 <0.02 1074477 77 48 20 12 0.1 1074606 31 10 64 <0.02 1074638 14 4 3 3 <0.02 1074766 72 32 14 7 0.1 1074798 34 12 5 6<0.02 1075118 85 36 8 4 0.1 1075246 70 34 12 6 0.1 1076174 58 21 7 4<0.02 1076366 63 25 8 4 0.04 1076430 42 14 6 4 <0.02 1076462 61 22 8 50.03 1076494 34 7 3 2 <0.02 1076526 44 9 3 2 <0.02

TABLE 73 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 103 89 85 87 >2.0 1074351 69 3313 7 0.1 1074447 47 20 8 5 <0.02 1074448 54 13 4 3 <0.02 1074479 23 8 44 <0.02 1074480 33 9 5 3 <0.02 1074607 45 22 10 5 <0.02 1074639 46 18 75 <0.02 1075055 60 20 6 4 0.03 1075088 37 9 4 2 <0.02 1075824 33 10 5 3<0.02 1075855 65 30 12 8 0.1 1075983 81 46 17 6 0.1 1076015 70 37 15 90.1 1076143 81 48 20 9 0.1 1076367 31 10 4 3 <0.02 1076399 60 29 11 60.04 1076464 36 10 3 2 <0.02 1076527 81 41 16 8 0.1

TABLE 74 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 33 5 3 2 <0.02 1074417 68 26 73 0.1 1074576 69 41 14 9 0.1 1074577 33 10 4 3 <0.02 1074608 49 20 9 7<0.02 1074609 65 29 15 11 0.1 1074672 34 18 10 7 <0.02 1074736 34 12 7 7<0.02 1074737 50 21 8 6 <0.02 1074800 48 21 10 7 <0.02 1074801 76 41 1912 0.1 1075089 45 9 3 3 <0.02 1075249 77 37 16 8 0.1 1075792 79 41 15 100.1 1076017 59 25 9 5 0.03 1076049 61 16 13 6 <0.02 1076369 60 20 6 3<0.02 1076370 46 12 4 2 <0.02 1076465 72 32 14 7 0.1

TABLE 75 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 27 5 2 2 <0.02 1074290 49 17 97 <0.02 1074418 55 26 9 4 <0.02 1074419 48 15 5 3 <0.02 1074420 38 8 3 2<0.02 1074450 54 22 7 5 <0.02 1074451 63 26 8 4 0.04 1074484 43 12 5 3<0.02 1074578 66 30 18 11 0.1 1074579 54 22 8 5 <0.02 1074610 57 20 10 7<0.02 1074675 47 18 6 3 <0.02 1075155 51 15 6 4 <0.02 1075699 26 6 3 2<0.02 1076114 34 11 6 5 <0.02 1076115 47 17 9 6 <0.02 1076466 43 18 8 6<0.02 1076467 24 6 3 2 <0.02 1076530 53 26 11 7 <0.02

TABLE 76 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 36 5 2 2 <0.02 1074229 58 24 95 <0.02 1074421 61 29 8 5 0.04 1074452 88 28 9 5 0.1 1074453 51 18 9 5<0.02 1074485 47 14 5 3 <0.02 1074548 50 15 7 8 <0.02 1074549 67 31 12 70.1 1074580 55 18 8 5 <0.02 1074613 63 23 9 6 0.04 1074676 54 16 6 5<0.02 1075061 58 23 9 6 <0.02 1075093 74 26 7 4 0.1 1075701 84 34 11 60.1 1075797 43 11 4 3 <0.02 1075893 80 29 11 8 0.1 1076084 69 34 12 80.1 1076085 70 34 14 9 0.1 1076340 79 42 17 11 0.1

TABLE 77 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 958499 37 4 2 2 <0.02 1074230 62 30 128 0.05 1074454 39 9 3 3 <0.02 1074486 55 26 10 6 <0.02 1074487 73 28 116 0.1 1074678 73 37 16 10 0.1 1074679 52 16 6 5 <0.02 1074775 26 5 2 2<0.02 1075222 75 30 8 5 0.1 1075766 56 21 11 8 <0.02 1075990 28 6 3 3<0.02 1076022 63 28 8 5 0.04 1076023 60 18 5 3 <0.02 1076119 82 35 12 60.1 1076183 65 22 9 6 0.04 1076406 51 20 9 7 <0.02 1076439 48 13 6 5<0.02 1076471 64 29 9 5 0.05 1076534 88 48 20 10 0.2

Example 9 Dose-Dependent Inhibition of Human Yap1 in SNU-449 Cells byModified Oligonucleotides

Modified oligonucleotides described in the studies above were tested atvarious doses in SNU-449 cells. Cultured SNU-449 cells at a density of10,000 cells per well were treated using free uptake with modifiedoligonucleotides diluted to concentrations described in the tablesbelow. After approximately 48 hours, Yap1 mRNA levels were measured aspreviously described using the Human Yap1 primer-probe set RTS36584.Yap1 mRNA levels were normalized to total RNA content, as measured byRIBOGREEN®. Results are presented in the tables below as percent controlof the amount of Yap1 mRNA relative to untreated control cells (% UTC).IC50s were calculated using a linear regression on a log/linear plot ofthe data in excel.

TABLE 78 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 94 47 23 8 0.2 1198371 85 66 4621 0.3 1198380 72 55 27 11 0.1 1198382 77 56 36 18 0.2 1198384 76 50 2417 0.1 1198397 70 53 28 14 0.1 1198398 73 55 33 18 0.2 1198406 70 57 3116 0.2 1198409 100 68 45 27 0.4 1198412 73 54 33 15 0.2 1198422 88 60 3019 0.2 1198423 58 35 15 6 0.05 1198424 64 44 24 9 0.1 1198438 62 28 7 20.04 1198439 44 21 5 2 <0.03 1198440 55 23 6 2 <0.03 1198718 87 37 14 40.1 1198719 67 30 9 3 0.1 1198746 49 24 9 3 <0.03

TABLE 79 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 90 44 15 5 0.1 1198202 83 46 165 0.1 1198212 74 35 10 2 0.1 1198213 91 33 11 3 0.1 1198638 70 42 13 40.1 1198641 55 29 11 3 0.03 1198642 79 48 15 4 0.1 1198656 55 22 8 3<0.03 1198664 52 33 14 5 <0.03 1198673 51 26 8 3 <0.03 1198696 58 31 112 0.04 1198697 60 29 7 1 0.04 1198698 55 29 8 2 0.03 1198724 56 25 8 3<0.03 1198728 51 28 9 3 <0.03 1198786 63 32 11 2 0.1 1198787 68 21 6 10.05 1198788 64 30 7 2 0.1 1198799 62 35 13 4 0.1

TABLE 80 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 98 56 25 10 0.2 958590 69 52 2912 0.1 1074728 69 45 19 8 0.1 1097247 58 28 8 2 0.04 1197215 56 31 7 20.04 1197216 66 39 15 4 0.1 1197217 66 39 14 4 0.1 1198285 67 41 16 50.1 1198286 64 45 22 8 0.1 1198287 95 68 36 16 0.3 1198288 77 43 17 70.1 1198289 72 41 18 9 0.1 1198290 60 39 20 10 0.1 1198294 59 33 14 50.05 1198295 82 47 19 8 0.1 1198297 67 42 16 7 0.1 1198347 67 54 24 80.1 1198354 66 24 5 1 0.05 1198356 85 30 7 1 0.1

TABLE 81 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 109 53 28 12 0.3 1198352 58 2910 3 0.04 1198353 60 30 10 4 0.04 1198355 63 34 10 4 0.1 1198358 68 3920 8 0.1 1198365 59 38 15 5 0.1 1198543 75 42 19 6 0.1 1198546 70 42 186 0.1 1198550 73 56 30 13 0.2 1198552 72 46 23 9 0.1 1198553 65 38 19 60.1 1198554 72 46 22 8 0.1 1198555 73 40 19 9 0.1 1198557 81 52 26 110.2 1198569 71 45 22 14 0.1 1198570 58 33 16 9 0.04 1198578 73 45 25 120.1 1198610 69 29 7 2 0.1 1198613 80 25 7 2 0.1

TABLE 82 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 125 73 35 15 0.4 1197229 54 3216 7 0.03 1197235 64 36 16 5 0.1 1197236 64 46 25 14 0.1 1197269 48 21 71 <0.03 1197270 43 23 8 2 <0.03 1197312 101 58 34 11 0.3 1197313 71 3816 6 0.1 1198596 73 40 14 4 0.1 1198605 57 27 7 1 0.03 1198611 37 19 4 1<0.03 1198612 44 12 2 0 <0.03 1198614 69 26 3 1 0.1 1198615 52 23 5 2<0.03 1198616 78 46 18 5 0.1 1198623 48 24 5 1 <0.03 1198624 62 37 21 90.1 1200797 84 52 23 11 0.2 1200798 77 44 17 7 0.1

TABLE 83 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 136 70 35 10 0.4 958499 93 4719 7 0.2 1074461 76 37 15 5 0.1 1197271 70 47 19 8 0.1 1197309 91 63 309 0.2 1200784 70 51 26 12 0.1 1200785 98 73 42 24 0.4 1200788 61 38 19 90.1 1200789 60 32 15 5 0.05 1200794 85 59 31 13 0.2 1200796 69 47 25 120.1 1200803 72 52 34 18 0.2 1200806 91 54 34 18 0.2 1200820 104 69 36 170.3 1200857 66 30 8 2 0.1 1200858 71 39 14 4 0.1 1200860 59 35 15 5 0.051200861 74 43 17 4 0.1 1200862 88 64 35 13 0.2

TABLE 84 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 100 62 29 12 0.3 1074462 90 3813 3 0.1 1074464 109 50 19 6 0.2 1198804 71 48 19 5 0.1 1198805 61 42 207 0.1 1198814 63 25 6 3 0.04 1198815 84 64 34 15 0.2 1198818 68 33 15 50.1 1198831 74 33 10 4 0.1 1198832 77 53 23 13 0.1 1198856 72 55 24 70.1 1198857 78 44 13 4 0.1 1198873 38 12 2 0 <0.03 1198874 36 8 1 0<0.03 1198875 61 23 4 1 0.04 1198895 62 37 16 9 0.1 1198911 62 31 12 70.05 1198917 81 37 12 6 0.1 1198918 60 33 13 9 0.05

TABLE 85 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 103 56 25 10 0.2 1009325 59 3616 4 0.1 1009326 59 35 14 4 0.05 1074756 42 20 6 3 <0.03 1074798 62 3817 8 0.1 1076187 68 46 24 12 0.1 1076453 67 29 8 1 0.1 1076481 86 40 153 0.1 1197176 66 37 19 6 0.1 1197177 56 29 8 2 0.03 1197178 64 36 14 40.1 1197179 58 38 17 7 0.1 1197193 85 52 24 11 0.2 1197213 87 46 14 20.1 1197214 88 31 7 1 0.1 1197223 88 55 25 8 0.2 1198312 76 34 10 5 0.11198872 49 21 6 1 <0.03 1198877 62 32 13 5 0.05

TABLE 86 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 92 53 22 12 0.2 1095481 73 4716 8 0.1 1095593 73 44 27 10 0.1 1198203 71 51 25 11 0.1 1198211 72 3723 12 0.1 1198243 55 28 10 5 <0.03 1198267 78 44 15 3 0.1 1198268 83 5217 5 0.1 1198457 82 56 31 12 0.2 1198460 60 49 28 11 0.1 1198466 68 4418 6 0.1 1198470 73 41 18 9 0.1 1198484 80 45 24 12 0.1 1198501 65 36 1711 0.1 1198524 50 32 9 3 <0.03 1198525 62 26 8 1 0.04 1198526 61 30 8 20.04 1198527 63 35 12 3 0.1 1198905 75 43 21 6 0.1

TABLE 87 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-449 cells % UTC IC50 ION No. 31.3 nM125.0 nM 500.0 nM 2000.00 nM (μM) 715487 89 48 23 10 0.2 1198492 67 3919 10 0.1 1198494 59 37 24 13 0.1 1198499 89 42 30 12 0.2 1198500 72 5134 15 0.2 1198502 76 50 29 15 0.2 1198504 77 46 27 24 0.1 1198507 83 5729 13 0.2 1198510 71 44 18 6 0.1 1198528 87 54 30 11 0.2 1198529 86 6937 16 0.3 1198900 69 36 18 7 0.1 1198902 74 46 22 10 0.1 1198904 78 3623 10 0.1 1198935 50 46 23 11 0.04 1198958 68 39 16 5 0.1 1198959 62 288 2 0.04 1198960 77 35 8 2 0.1 1198961 77 35 11 3 0.1

Example 10 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male Balb/c mice at 4-6 weeks of age (obtained from Taconic)were injected subcutaneously twice a week for four weeks (for a total of8 treatments) with 50 mg/kg of modified oligonucleotides. One group ofmale Balb/c mice was injected with PBS. Mice were euthanized on day 26post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), and total bilirubin (TBIL) were measured usingan automated clinical chemistry analyzer (Hitachi Olympus AU400c,Melville, N.Y.). The results are presented in the table below. Modifiedoligonucleotides that caused changes in the levels of any of the liveror kidney function markers outside the expected range for modifiedoligonucleotides were excluded in further studies.

TABLE 88 Plasma chemistry markers in Balb/c mice ALT AST TBIL ION No.(U/L) (U/L) (mg/dL) PBS 35 56 0.18 715480 791 439 0.15 715484 116 1100.15 715487 79 96 0.13 715491 33 48 0.11 715557 1755 2377 0.28 715558 6591 0.16 715582 2460 2320 2.09 715593 628 610 0.11 715609 1120 2941 0.67715659 332 431 0.23 715744 164 138 0.15 715763 522 316 0.18 715766 182191 0.12 715784 47 47 0.13 715797 188 222 0.15 715859 306 133 0.17715863 2090 903 0.54Body and Organ Weights

Body weights of Balb/c mice were measured at the end of the study, andthe average body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 89 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 22 1.05 0.37 0.09 715480 22 1.64 0.34 0.12 715484 221.47 0.37 0.13 715487 23 1.24 0.36 0.14 715491 22 1.03 0.32 0.12 71555721 1.96 0.31 0.12 715558 22 1.33 0.38 0.12 715582 22 1.46 0.38 0.16715593 19 1.12 0.30 0.13 715609 21 2.64 0.33 0.10 715659 20 1.21 0.310.11 715744 22 1.18 0.32 0.17 715763 23 1.71 0.36 0.13 715766 21 1.400.30 0.12 715784 23 1.15 0.39 0.12 715797 22 1.39 0.36 0.16 715859 221.32 0.36 0.14 715863 21 1.79 0.33 0.12

Example 11 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male Balb/c mice at 4-6 weeks of age (obtained from Taconic)were injected subcutaneously twice a week for four weeks (for a total of8 treatments) with 50 mg/kg of modified oligonucleotides. One group ofmale Balb/c mice was injected with PBS. Mice were euthanized on day 26post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) weremeasured using an automated clinical chemistry analyzer (Hitachi OlympusAU400c, Melville, N.Y.). The results are presented in the table below.Modified oligonucleotides that caused changes in the levels of any ofthe liver or kidney function markers outside the expected range formodified oligonucleotides were excluded in further studies.

TABLE 90 Plasma chemistry markers in Balb/c mice ALT AST BUN TBIL IONNo. (U/L) (U/L) (mg/dL) (mg/dL) PBS 18 54 14 0.18 715415 1075 701 170.14 715473 3046 2861 20 2.77 715483 62 70 16 0.17 715487 59 81 16 0.18716424 2077 1422 20 0.22 716454 39 60 14 0.18 716455 1089 1193 22 0.25716480 2156 844 19 0.14 716481 1935 2248 21 0.46 716502 2920 1329 170.27 716513 325 229 17 0.14Body and Organ Weights

Body weights of Balb/c mice were measured at the end of the study, andthe average body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 91 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 24 1.09 0.40 0.11 715415 25 1.79 0.40 0.17 715473 201.46 0.31 0.09 715483 25 1.56 0.43 0.12 715487 27 1.46 0.42 0.15 71642423 2.08 0.36 0.15 716454 25 1.48 0.42 0.14 716455 21 2.66 0.32 0.14716480 21 2.58 0.34 0.10 716481 22 1.99 0.36 0.13 716502 23 2.18 0.420.10 716513 25 1.59 0.41 0.18

Example 12 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male Balb/c mice at 6-7 weeks of age (obtained from Taconic)were injected subcutaneously twice a week for four weeks (for a total of8 treatments) with 50 mg/kg of modified oligonucleotides. One group ofmale Balb/c mice was injected with PBS. Mice were euthanized on day 26post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) weremeasured using an automated clinical chemistry analyzer (Hitachi OlympusAU400c, Melville, N.Y.). The results are presented in the table below.Modified oligonucleotides that caused changes in the levels of any ofthe liver or kidney function markers outside the expected range formodified oligonucleotides were excluded in further studies.

TABLE 92 Plasma chemistry markers in Balb/c mice ALT AST TBIL BUN IONNo. (U/L) (U/L) (mg/dL) (mg/dL) PBS 22 63 0.16 22 958375 2736 3013 0.4322 958454 1183 2162 6.53 45 958498 1441 3197 0.74 12 958499 142 146 0.1726 958509 1483 1627 0.31 26 958540 4127 3940 0.44 25 958553 174 227 0.2029 958554 583 1051 0.28 17 958590 374 360 0.16 25 958603 1103 927 0.3527 958721 57 114 0.17 28 958725 3758 3758 0.91 31 958729 4368 4503 2.1530 958736 2439 1450 0.31 20Body and Organ Weights

Body weights of Balb/c mice were measured at the end of the study, andthe average body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 93 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 24 1.28 0.37 0.09 958375 23 2.00 0.39 0.12 958454 140.68 0.25 0.03 958498 20 1.51 0.45 0.19 958499 23 1.44 0.32 0.14 95850920 1.50 0.27 0.13 958540 19 1.53 0.33 0.09 958553 21 1.01 0.29 0.11958554 22 1.05 0.28 0.15 958590 25 1.76 0.40 0.13 958603 21 1.80 0.360.20 958721 24 1.45 0.33 0.12 958725 15 1.23 0.21 0.04 958729 15 1.320.24 0.05 958736 24 1.95 0.39 0.18

Example 13 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male Balb/c mice at 4-6 weeks of age (obtained from Taconic)were injected subcutaneously twice a week for four weeks (for a total of8 treatments) with 50 mg/kg of modified oligonucleotides. One group ofmale Balb/c mice was injected with PBS. Mice were euthanized on day 25post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) weremeasured using an automated clinical chemistry analyzer (Hitachi OlympusAU400c, Melville, N.Y.). The results are presented in the table below.Modified oligonucleotides that caused changes in the levels of any ofthe liver or kidney function markers outside the expected range formodified oligonucleotides were excluded in further studies.

TABLE 94 Plasma chemistry markers in Balb/c mice ALT AST TBIL BUN IONNo. (U/L) (U/L) (mg/dL) (mg/dL) PBS   26*   65* 0.18 22 958371  249  1990.24 30 958914  1855 1837 0.68 29 958933   63  122 0.22 33 958939  22361863 0.38 23 958941  772  500 0.23 30 958961   66  106 0.19 28 958973  93  126 0.20 22 959022 13242 8058 1.12 25 959030  1160 1328 0.21 29959155  2146 1686 0.22 26 959167  1556 2096 0.56 24 959196  1169  7850.31 27 959197  753  493 0.29 23 *Average of 3 valuesBody and Organ Weights

Body weights of Balb/c mice were measured at the end of the study, andthe average body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 95 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 25 1.29 0.39 0.09 958371 23 1.31 0.32 0.15 958914 191.22 0.32 0.12 958933 27 1.86 0.37 0.15 958939 24 1.67 0.40 0.23 95894126 1.81 0.37 0.15 958961 26 1.47 0.39 0.15 958973 26 1.71 0.40 0.19959022 19 1.76 0.34 0.11 959030 25 1.73 0.38 0.14 959155 21 1.53 0.340.25 959167 22 0.96 0.37 0.10 959196 23 1.22 0.34 0.11 959197 23 1.370.34 0.14

Example 14 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male Balb/c mice at 5-6 weeks of age (obtained from Taconic)were injected subcutaneously twice a week for four weeks (for a total of8 treatments) with 50 mg/kg of modified oligonucleotides. One group ofmale Balb/c mice was injected with PBS. Mice were euthanized on day 27post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) weremeasured using an automated clinical chemistry analyzer (Hitachi OlympusAU400c, Melville, N.Y.). The results are presented in the table below.Modified oligonucleotides that caused changes in the levels of any ofthe liver or kidney function markers outside the expected range formodified oligonucleotides were excluded in further studies.

TABLE 96 Plasma chemistry markers in Balb/c mice ALT AST TBIL BUN IONNo. (U/L) (U/L) (mg/dL) (mg/dL) PBS 33 123 0.25 22 958497 46 151 0.24 26958534 1962 1617 0.33 26 958589 35 66 0.21 24 958596 207 162 0.23 24958622 224 254 0.24 23 958739 145 186 0.21 21Body and Organ Weights

Body weights of Balb/c mice were measured on day 25, and the averagebody weight for each group is presented in the table below. Kidney,spleen, and liver weights were measured at the end of the study and arepresented in the table below. Modified oligonucleotides that caused anychanges in organ weights outside the expected range for modifiedoligonucleotides were excluded from further studies.

TABLE 97 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 23 1.14 0.35 0.08 958497 23 1.31 0.35 0.11 958534 221.81 0.32 0.09 958589 25 1.40 0.37 0.10 958596 25 2.11 0.36 0.13 95862223 0.92 0.33 0.12 958739 24 1.58 0.36 0.13

Example 15 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 4-5 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 8 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized onday 26 post start of treatment (24 hrs following the finaladministration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), albumin (ALB) and totalbilirubin (TBIL) were measured using an automated clinical chemistryanalyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results arepresented in the table below. Modified oligonucleotides that causedchanges in the levels of any of the liver or kidney function markersoutside the expected range for modified oligonucleotides were excludedin further studies.

TABLE 98 Plasma chemistry markers in CD-1 mice ALT AST TBIL BUN ALB IONNo. (U/L) (U/L) (mg/dL) (mg/dL) (g/dL) PBS 32 47 19 0.2 2.5 1074234 81187 23 0.2 2.3 1074461 1563 865 22 0.6 2.2 1074554 32 49 22 0.2 2.51074557 32 65 23 0.2 2.3 1074587 163 131 25 0.2 2.4 1074588 38 67 22 0.22.3 1074622 34 59 20 0.2 2.5 1074655 1360 978 19 0.3 2.0 1074680 78 12519 0.1 2.0 1075067 28 59 23 6.4 2.5 1075068 43 81 19 0.2 2.2 1075741 114113 20 0.2 2.3 1075768 48 65 19 0.2 2.3 1075769 74 103 18 0.2 2.51075774 45 71 20 0.2 2.5 1075838 97 131 22 0.2 2.2 715483 79 125 21 0.22.2 715487 66 113 21 0.1 1.9 716454 44 56 20 0.2 2.3Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 99 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 44 2.51 0.61 0.12 1074234 37 2.26 0.55 0.12 107455438 2.09 0.52 0.11 1074557 38 1.87 0.61 0.15 1074587 39 2.33 0.58 0.161074588 40 2.40 0.69 0.20 1074622 38 2.16 0.64 0.21 1074655 39 3.40 0.690.30 1074680 42 2.52 0.65 0.24 1075067 40 2.12 0.65 0.17 1075068 38 2.150.64 0.20 1075741 39 2.21 0.62 0.23 1075768 37 1.86 0.54 0.13 1075769 351.76 0.47 0.10 1075774 37 2.23 0.59 0.14 1075838 41 2.28 0.57 0.25715483 40 2.26 0.64 0.21 715487 41 2.24 0.59 0.21 716454 38 2.31 0.550.20

Example 16 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 4-5 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 8 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized onday 27 post start of treatment (24 hrs following the finaladministration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), albumin (ALB) and totalbilirubin (TBIL) were measured using an automated clinical chemistryanalyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results arepresented in the table below. Modified oligonucleotides that causedchanges in the levels of any of the liver or kidney function markersoutside the expected range for modified oligonucleotides were excludedin further studies.

TABLE 100 Plasma chemistry markers in CD-1 mice ALT AST TBIL BUN AlbuminION No. (U/L) (U/L) (mg/dL) (mg/dL) (g/dL) PBS 21 45 0.19 22 2.5 107602441 88 0.19 19 2.3 1076157 55 105 0.19 19 2.1 1076186 74 97 0.16 23 2.51076187 57 90 0.18 20 2.3 1076190 48 63 0.17 20 2.2 1076287 53 98 0.2021 2.1 1076379 37 89 0.15 20 2.1 1076382 52 87 0.14 19 1.9 1076475 38 620.15 18 2.0 1095493 1623 1449 0.69 18 1.8Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 101 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 35 1.78 0.56 0.12 1076024 40 2.28 0.66 0.15 107615738 2.48 0.58 0.23 1076186 37 2.42 0.58 0.16 1076187 34 1.95 0.56 0.141076190 38 2.28 0.56 0.15 1076287 36 2.36 0.63 0.36 1076379 38 2.21 0.570.18 1076382 36 2.22 0.62 0.21 1076475 37 2.16 0.64 0.17 1095493 28 1.940.50 0.17

Example 17 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 4-5 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 8 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized onday 27 post start of treatment (24 hrs following the finaladministration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), albumin (ALB) and totalbilirubin (TBIL) were measured using an automated clinical chemistryanalyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results arepresented in the table below. Modified oligonucleotides that causedchanges in the levels of any of the liver or kidney function markersoutside the expected range for modified oligonucleotides were excludedin further studies.

TABLE 102 Plasma chemistry markers in CD-1 mice ALT AST BUN TBIL ION No.(U/L) (U/L) (mg/dL) (mg/dL) PBS 22 100 24 0.16 1095404 1282 503 22 0.141095515 1041 951 19 1.12 1095632 92 126 26 0.15 1096947 46 116 23 0.171096450 1104 635 25 2.19 1096973 35 59 20 0.22 1097037 73 97 23 0.121096522 652 397 21 0.16 1075395 38 51 21 0.18 1097183 834 738 16 0.391097224 39 78 21 0.09 1097231 85 112 21 0.13Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 103 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 34 1.92 0.55 0.11 1095404 33 2.09 0.58 0.15 109551526 1.52 0.47 0.20 1095632 33 2.04 0.48 0.17 1096947 33 1.91 0.51 0.211096450 35 2.59 0.42 0.19 1096973 35 2.21 0.48 0.18 1097037 33 2.33 0.520.21 1096522 31 2.04 0.45 0.18 1075395 34 2.30 0.49 0.20 1097183 28 1.230.46 0.20 1097224 37 1.93 0.54 0.16 1097231 34 2.37 0.47 0.24

Example 18 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 5-6 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 9 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized onday 34 post start of treatment (24 hours following the finaladministration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), albumin (ALB) and totalbilirubin (TBIL) were measured using an automated clinical chemistryanalyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results arepresented in the table below. Modified oligonucleotides that causedchanges in the levels of any of the liver or kidney function markersoutside the expected range for modified oligonucleotides were excludedin further studies.

TABLE 104 Plasma chemistry markers in CD-1 mice ALT AST BUN TBIL ION No.(U/L) (U/L) (mg/dL) (mg/dL) PBS 24 53 20 0.27  958499 79 88 24 0.181074755 88 104 22 0.21 1076453 56 113 20 0.24 1076481 71 121 23 0.23Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 105 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 39 1.84 0.59 0.17  958499 39 2.20 0.57 0.22 107475539 2.27 0.61 0.19 1076453 38 1.91 0.56 0.20 1076481 39 2.06 0.57 0.23

Example 19 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 4-6 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 8 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized onday 26 post start of treatment (24 hrs following the finaladministration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), albumin (ALB) and totalbilirubin (TBIL) were measured using an automated clinical chemistryanalyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results arepresented in the table below. Modified oligonucleotides that causedchanges in the levels of any of the liver or kidney function markersoutside the expected range for modified oligonucleotides were excludedin further studies.

TABLE 106 Plasma chemistry markers in CD-1 mice ALT AST TBIL BUN ION No.(U/L) (U/L) (mg/dL) (mg/dL) PBS 32 48 0.25 20 1198439 210 219 0.25 181198440 121 140 0.22 19 1198872 192 207 0.25 22 1157929 39 50 0.22 191157034 210 165 0.19 17 1157111 48 74 0.22 17Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 107 Body and organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 36 2.04 0.59 0.12 1198439 36 2.03 0.51 0.25 119844035 1.97 0.46 0.18 1198872 34 1.84 0.40 0.16 1157929 34 1.98 0.43 0.131157034 35 2.43 0.53 0.17 1157111 36 2.53 0.50 0.21

Example 20 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in Sprague-Dawley Rats

Sprague-Dawley rats are a multipurpose model used for safety andefficacy evaluations. The rats were treated with Ionis modifiedoligonucleotides from the studies described in the Examples above andevaluated for changes in the levels of various plasma chemistry markers.

Treatment

Male Sprague-Dawley rats were maintained on a 12-hour light/dark cycleand fed ad libitum with Purina normal rat chow. Groups of 4Sprague-Dawley rats each were weekly injected subcutaneously with 50mg/kg of Ionis oligonucleotide for 6 weeks (total 7 doses). Forty-eighthours after the last dose, the rats were euthanized; and organs, urineand plasma were harvested for further analysis.

Plasma Chemistry Markers

To evaluate the effect of Ionis oligonucleotides on hepatic function,plasma levels of transaminases were measured using an automated clinicalchemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasmalevels of ALT (alanine transaminase) and AST (aspartate transaminase)were measured and the results are presented in the table below expressedin IU/L. Plasma levels of total bilirubin (TBIL), albumin (ALB), andblood urea nitrogen (BUN) were also measured using the same clinicalchemistry analyzer and the results are also presented in the tablebelow. Ionis modified oligonucleotides that caused changes in the levelsof any markers of liver function outside the expected range for modifiedoligonucleotides were excluded in further studies.

TABLE 108 Plasma chemistry markers in Sprague-Dawley rats Plasmaclinical chemistry ALT AST TBIL BUN ALB ASO (U/L) (U/L) (mg/dL) (mg/dL)(g/dL) PBS  31*  67*  0.17* 16 1.61  958499 61 109 0.18 24 2.78 107475557  97 0.12 29 2.99 1076187 54 113 0.10 21 2.91 1076453 47  77 0.13 233.14 1076481 50  91 0.13 49 2.74 1097224 31  51 0.07 86 1.61 *Refers togroups with only 3 data pointsKidney Function

To evaluate the effect of Ionis oligonucleotides on kidney function,urinary levels of total protein and creatinine were measured using anautomated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville,N.Y.). The ratios of total protein to creatinine (P/C ratio) arepresented in the Table below. Ionis oligonucleotides that caused changesin the levels of the ratio outside the expected range for modifiedoligonucleotides were excluded in further studies.

TABLE 109 Total protein to creatinine ratio in Sprague-Dawley rats URINEP/C ION NO. ratio PBS 1  958499 5 1074755 5 1076187 5 1076453 5 10764815 1097224 87Body and Organ Weights

Liver, spleen and kidney weights were measured at the end of the studyand are presented in the table below. Terminal body weight was measuredprior to necropsy. Ionis oligonucleotides that caused any changes inorgan weights outside the expected range for modified oligonucleotideswere excluded from further studies.

TABLE 110 Body and Organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 423 16 3.1 0.9  958499 333 14 3.1 2.8 1074755 357 163.3 2.1 1076187 344 17 3.0 1.7 1076453 371 16 3.2 2.1 1076481 367 14 2.62.1 1097224 316 13 4.5 1.4

Example 21 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in Sprague-Dawley Rats

Sprague-Dawley rats are a multipurpose model used for safety andefficacy evaluations. The rats were treated with Ionis modifiedoligonucleotides from the studies described in the Examples above andevaluated for changes in the levels of various plasma chemistry markers.

Treatment

Male Sprague-Dawley rats were maintained on a 12-hour light/dark cycleand fed ad libitum with Purina normal rat chow. Groups of 4Sprague-Dawley rats each were weekly injected subcutaneously with 50mg/kg of Ionis oligonucleotide for 6 weeks (total 7 doses). Forty-eighthours after the last dose, the rats were euthanized; and organs, urineand plasma were harvested for further analysis.

Plasma Chemistry Markers

To evaluate the effect of Ionis oligonucleotides on hepatic function,plasma levels of transaminases were measured using an automated clinicalchemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasmalevels of ALT (alanine transaminase) and AST (aspartate transaminase)were measured and the results are presented in the Table below expressedin IU/L. Plasma levels of total bilirubin (TBIL) and blood urea nitrogen(BUN) were also measured using the same clinical chemistry analyzer andthe results are also presented in the Table below. Ionis modifiedoligonucleotides that caused changes in the levels of any markers ofliver function outside the expected range for modified oligonucleotideswere excluded in further studies.

TABLE 111 Plasma chemistry markers in Sprague-Dawley rats Plasmaclinical chemistry ALT AST TBIL BUN ASO (U/L) (U/L) (mg/dL) (mg/dL) PBS 64 98  0.19 19 1198874  73 102  0.16 22 1200857 183 318  4.93 561074756  114* 79*  0.10*    0.57* 1198873  78* 79*  0.17*  24* 1198439 54* 94*  0.15*  22* 1198615  38 71  0.13 21 1198440   58** 108** 0.17**  20** 1198612  74 91  0.12 31 1198312 132 108  0.14 25 *Refersto groups with 3 samples **Refers to groups with 2 samplesBody and Organ Weights

Liver, spleen and kidney weights were measured at the end of the studyand are presented in the table below. Terminal body weight was measuredprior to necropsy. Ionis oligonucleotides that caused any changes inorgan weights outside the expected range for modified oligonucleotideswere excluded from further studies.

TABLE 112 Body and Organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 453 17 3.64 0.91 1198874 372 20 3.67 2.61 1200857307 19 6.97 2.55 1074756 349  21*  4.71*  1.99* 1198873 408 19 3.65 2.421198439  319*  17*  3.68*  2.28* 1198615 369 16 3.01 2.35 1198440 373 183.29 2.78 1198612 345 17 3.60 2.33 1198312 365 19 4.26 2.19 *Refers togroups with 3 samplesKidney Function

To evaluate the effect of Ionis oligonucleotides on kidney function,urinary levels of total protein and creatinine were measured using anautomated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville,N.Y.). The ratios of total protein to creatinine (P/C ratio) arepresented in the Table below. Ionis oligonucleotides that caused changesin the levels of the ratio outside the expected range for modifiedoligonucleotides were excluded in further studies.

TABLE 113 Total protein to creatinine ratio in Sprague-Dawley rats URINEP/C ION NO. ratio PBS  1 1198874  9 1200857  52 1074756 167 1198873  91198439   8* 1198615  8 1198440  9 1198612  11 1198312  60 *Refers togroups with 3 samples

Example 22 Tolerability of Modified Oligonucleotides Targeting HumanYap1 in Sprague-Dawley Rats

Sprague-Dawley rats are a multipurpose model used for safety andefficacy evaluations. The rats were treated with Ionis modifiedoligonucleotides from the studies described in the Examples above andevaluated for changes in the levels of various plasma chemistry markers.

Treatment

Male Sprague-Dawley rats were maintained on a 12-hour light/dark cycleand fed ad libitum with Purina normal rat chow. Groups of 4Sprague-Dawley rats each were weekly injected subcutaneously with 50mg/kg of Ionis oligonucleotide for 6 weeks (total 7 doses). Forty-eighthours after the last dose, the rats were euthanized; and organs, urineand plasma were harvested for further analysis.

Plasma Chemistry Markers

To evaluate the effect of Ionis oligonucleotides on hepatic function,plasma levels of transaminases were measured using an automated clinicalchemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasmalevels of ALT (alanine transaminase) and AST (aspartate transaminase)were measured and the results are presented in the Table below expressedin IU/L. Plasma levels of total bilirubin (TBIL) and blood urea nitrogen(BUN) were also measured using the same clinical chemistry analyzer andthe results are also presented in the Table below. Ionis modifiedoligonucleotides that caused changes in the levels of any markers ofliver function outside the expected range for modified oligonucleotideswere excluded in further studies.

TABLE 114 Plasma chemistry markers in Sprague-Dawley rats Plasmaclinical chemistry ALT AST TBIL BUN ASO (U/L) (U/L) (mg/dL) (mg/dL) PBS80 105 0.22 19 1197270 84 120 0.19 24 1198872 109 134 0.20 18 1198728 5471 0.18 22 1198831 54 69 0.20 23 1198623 96 87 0.24 21 1198605 46 760.33 18Kidney Function

To evaluate the effect of Ionis oligonucleotides on kidney function,urinary levels of total protein and creatinine were measured using anautomated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville,N.Y.). The ratios of total protein to creatinine (P/C ratio) arepresented in the Table below. Ionis oligonucleotides that caused changesin the levels of the ratio outside the expected range for modifiedoligonucleotides were excluded in further studies.

TABLE 115 Total protein to creatinine ratio in Sprague-Dawley rats URINEP/C ION NO. ratio PBS 1 1197270 14 1198872 8 1198728 7 1198831 171198623 5 1198605 28Body and Organ Weights

Liver, spleen and kidney weights were measured at the end of the studyand are presented in the table below. Terminal body weight was measuredprior to necropsy. Ionis oligonucleotides that caused any changes inorgan weights outside the expected range for modified oligonucleotideswere excluded from further studies.

TABLE 116 Body and Organ weights body weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 476 18 3.4 0.9 1197270 374 15 3.6 2.0 1198872 417 173.4 1.3 1198728 381 15 2.9 1.4 1198831 426 19 3.3 2.0 1198623 472 20 3.61.9 1198605 372 18 3.6 2.1

Example 23 Measurement of Viscosity of Modified OligonucleotidesTargeting Human Yap1

The viscosity of select modified oligonucleotides from the studiesdescribed above was measured with the aim of screening out modifiedoligonucleotides which have a viscosity of more than 40 centipoise (cP).Modified oligonucleotides having a viscosity greater than 40 cP wouldhave less than optimal viscosity.

Oligonucleotides (32-38 mg) were weighed into a glass vial;approximately 100 μL of water was added, and the modifiedoligonucleotide was dissolved into solution by heating the vial to 55°C. Part (75 μL) of the pre-heated sample was pipetted to amicro-viscometer (PAC Cambridge Viscosity Viscometer). The temperatureof the micro-viscometer was set to 25° C. and the viscosity of thesample was measured. The entire 75 uL of sample was them combined withthe remaining portion of the sample was diluted appropriately for UVreading at 260 nM (Cary UV instrument). Modified oligonucleotidessolutions that were not optimal in their viscosity under the criterionstated above were excluded in further studies.

TABLE 117 Viscosity of modified oligonucleotides ConcentrationConcentration Compound by weight by UV Viscocity ID (mg/mL) (mg/mL) (cP)958499 300 220.7 84.5 1074755 300 217.2 7.2 1074756 300 232.8 17.41076187 300 237.4 40.6 1076453 300 229.1 46.4 1076481 300 213.0 6.41097224 300 230.7 8.1 1197269 300 211.4 10.7 1197270 300 241.6 15.11198243 300 234.0 13.4 1198312 300 233.1 17.5 1198439 300 233.8 141198440 300 219.7 8.6 1198501 300 220.0 14.5 1198605 300 220.7 59.61198611 300 228.3 8.6 1198612 300 230.1 10.2 1198615 300 223.1 231198623 300 215.4 20.8 1198641 300 223.2 16.4 1198656 300 227.6 26.11198673 300 237.2 15.3 1198728 300 241.8 30.9 1198746 300 232.7 13.41198831 300 204.0 5.8 1198872 300 220.7 5.5 1198873 300 229.1 7.61198874 300 222.0 12.5 1200857 300 226.4 13.1

Example 24 Dose-Dependent Inhibition of Human Yap1 in A-431 Cells byModified Oligonucleotides

Modified oligonucleotides described in the studies above were tested atvarious doses in A-431 cells. Cultured A-431 cells at a density of11,000 cells per well were treated using free uptake with modifiedoligonucleotides diluted to concentrations described in the tablesbelow. After approximately 48 hours, Yap1 mRNA levels were measured aspreviously described using the Human Yap1 primer-probe set RTS36584.Yap1 mRNA levels were normalized to GAPDH content, as measured by primerprobe set RTS104 (forward sequence GAAGGTGAAGGTCGGAGTC, designatedherein as SEQ ID NO.: 17; reverse sequence GAAGATGGTGATGGGATTTC,designated herein as SEQ ID NO.: 18; probe sequenceCAAGCTTCCCGTTCTCAGCC, designated herein as SEQ ID NO.: 19). Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC). IC50s were calculatedusing a linear regression on a log/linear plot of the data in excel.

TABLE 118 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 cells % UTC IC50 ION No. 0.002 μM0.008 μM 0.04 μM 0.2 μM 1 μM (μM) 958499 1 3 28 91 117 0.03 1076453 0 123 74 89 0.01 1197270 0 2 26 80 99 0.02 1198439 0 1 11 65 93 0.021198440 0 1 14 69 96 0.02 1198605 0 2 26 57 96 0.02 1198623 2 5 28 72 960.01 1198728 1 4 27 85 87 0.02 1198831 2 6 28 72 83 0.01 1198872 1 3 1970 94 0.01

Example 25 Activity of Modified Oligonucleotides Targeting Human Yap1 inSCC25 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in squamous cell carcinoma cell SCC25. A controloligonucleotide 792169 (a 3-10-3 cET gapmer with a full phosphorothioatebackbone, CGCCGATAAGGTACAC, designated herein as SEQ ID No.: 2940; isnot complementary to any known human gene) was also tested.

RNA Analysis

Cultured SCC25 cells at a density of 5,000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002 (forwardsequence CGGACTATGACTTAGTTGCGTTACA, designated herein as SEQ ID NO.: 20;reverse sequence GCCATGCCAATCTCATCTTGT, designated herein as SEQ ID NO.:21; probe sequence CCTTTCTTGACAAAACCTAACTTGCGCAGA, designated herein asSEQ ID NO.: 22). Results are presented in the tables below as percentcontrol of the amount of Yap1 mRNA relative to untreated control cells(% UTC).

TABLE 119 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SCC25 cells % UTC ION No. 0.04 μM 0.2 μM 1μM 5 μM 792169 96 89 93 98 958499 47 22 10 4 1076453 59 21 7 3 119727048 24 12 7 1198439 35 12 5 3 1198440 39 14 5 3 1198605 48 23 10 51198623 61 31 15 10 1198728 71 31 15 7 1198831 63 36 16 14 1198872 54 229 7Cell Proliferation Assay

Cultured SCC25 cells at a density of 1,000 cells/well were treated usingfree uptake with modified oligonucleotides diluted to concentrationsdescribed in the tables below. After approximately 144 hours, cellproliferation was measured using the luminescent cell viabilityCellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tablesbelow as percent control of the amount of luminescence in samplestreated with modified oligonucleotides relative to untreated controlcells (% UTC).

TABLE 120 Antiproliferative effect of modified oligonucleotides in SCC25cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 103 104 100 88958499 76 42 25 14 1076453 81 40 23 15 1197270 75 40 22 14 1198439 62 3022 16 1198440 73 33 22 16 1198605 77 39 23 13 1198623 84 55 36 291198728 88 61 30 20 1198831 88 54 25 21 1198872 82 37 22 18

Example 26 Dose Dependent Inhibition of Human Yap1 by ModifiedOligonucleotides in a Human Hepatocellular Carcinoma SNU449 XenograftTumor Model

A SNU449 hepatocellular carcinoma xenograft tumor model was used toevaluate activity of modified oligonucleotides targeted to human Yap1.Ten million SNU449 cells in 30% matrigel were implanted subcutaneouslyinto the flanks of female NOD Cg-Prkdcscid ll2rgtm1Wjl/SzJ (NSG) mice(from Jackson Laboratory) at 4-6 weeks of age. When tumors reached anaverage volume of 100 mm³, approximately two weeks post-implantation,groups of four mice each were administered at 50 mg/kg twice weekly withmodified oligonucleotides for five days. Tumors were collected andtested for Yap1 mRNA knockdown by RT-qPCR. Yap1 mRNA levels weremeasured as previously described using the Human Yap1 primer-probe setRTS4814. Yap1 mRNA levels were normalized to actin-beta content, asmeasured by primer probe set RTS5002. Results are presented in thetables below as percent control of the amount of Yap1 mRNA relative toPBS treated animals (% control).

TABLE 121 Inhibition of human Yap1 mRNA expression by modifiedoligonucleotides in SNU449 xenografts ION No. % control PBS 100  95849954 1074755 70 1076453 56 1197269 57 1197270 54 1198439 51 1198440 511198501 54 1198605 55 1198615 62 1198623 60 1198641 68 1198673 521198728 64 1198831 67 1198872 52  715487 61

Example 27 Dose Dependent Inhibition of Human Yap1 by ModifiedOligonucleotides in a Human Epidermoid Carcinoma A-431 Xenograft TumorModel

An epidermoid carcinoma A-431 xenograft tumor model was used to evaluateactivity of modified oligonucleotides targeted to human Yap1. Fivemillion A-431 cells in 30% matrigel were implanted subcutaneously intothe flanks of female NCr-Foxn1nu mice (from Taconic) at 4-6 weeks ofage. When tumors reached an average volume of 40 mm³, approximately twoweeks post-implantation, groups of four mice each were administered ateither 25 mg/kg or 50 mg/kg daily with modified oligonucleotides forfour days (5 doses). Tumors were collected 6-8 hours post final dose andtested for Yap1 mRNA knockdown by RT-qPCR. Yap1 mRNA levels weremeasured as previously described using the Human Yap1 primer-probe setRTS4814. Yap1 mRNA levels were normalized to actin-beta content, asmeasured by primer probe set RTS5002. Results are presented in thetables below as percent control of the amount of Yap1 mRNA relative toPBS treated animals (% control).

TABLE 122 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in A-431 xenografts % control ION No. 25 mpk50 mpk PBS 100 100  958499 49 29 1076453 55 25 1197270 57 38 1198439 3719 1198440 32 21 1198605 32 30 1198623 43 36 1198728 47 39 1198831 47 371198872 34 26  715487 61 57

Example 28 Dose Dependent Inhibition of Human Yap1 by ModifiedOligonucleotides in a Human Squamous Cell Carcinoma CAL27 XenograftTumor Model

A squamous cell carcinoma CAL27 xenograft tumor model was used toevaluate activity of modified oligonucleotides targeted to human Yap1.Five million CAL27 cells in 30% matrigel were implanted subcutaneouslyinto the flanks of female CrTac:NCr-Foxn1nu mice (from Taconic) at 4-6weeks of age. Groups of four mice each were administered with either 15mg/kg or 30 mg/kg of modified oligonucleotides daily for five days aftertumor size had reached ˜100 mm³ (about 3 weeks post implantation).Tumors were collected and tested for Yap1 mRNA knockdown by RT-qPCR.Yap1 mRNA levels were measured as previously described using the HumanYap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to PBS treated untreated control cells (% UTC).

TABLE 123 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in CAL27 xenografts % UTC ION No. 15 mg/kg 30mg/kg PBS 100 100  958499 68 53 1076453 69 46 1197270 55 38 1198439 6638 1198440 67 41 1198605 65 48 1198623 52 44 1198728 77 56 1198831 70 481198872 55 38

Example 29 Activity of Modified Oligonucleotides Targeting Human Yap1 ina Human Squamous Cell Carcinoma CAL33 Xenograft Tumor Model

A xenograft tumor model was used to evaluate activity of modifiedoligonucleotides targeted to human Yap1. One million CAL33 cells in 30%matrigel were implanted subcutaneously into the flanks of femaleCrTac:NCr-Foxnlnu (Taconic) mice. When tumors reached an average volumeof 100 mm³, approximately two weeks post-implantation, groups of eightmice were administered at 50 mg/kg twice weekly with modifiedoligonucleotides for two weeks. ION 792169 was administered as acontrol.

Tumor samples were collected for measurement of Yap1 mRNA levels byRT-qPCR. Yap1 mRNA levels were measured as previously described usingthe Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels werenormalized to actin-beta content, as measured by primer probe setRTS5002. Results are presented in the tables below as percent control ofthe amount of Yap1 mRNA relative to PBS treated animals (% control).

Tumor volume was measured at the indicated days in the table below.Tumor weight was determined at end of study. Mice were sacrificed whentumors from PBS-treated mice reached 2,000 mm3.

TABLE 124 Yap1 mRNA levels in tumors ION No. % control PBS 102  79216974 1198728 40 1198440 12

TABLE 125 Tumor volume (mm³) Days post-implantation 10 13 17 21 24 27 3134 38 40 44 ION Number Average Tumor Volume(mm³) PBS 144 254 382 666 855974 1180 1342 1458 1472 1377  792169 123 262 367 531 774 805 962 10571171 1160 1069 1198728 113 253 423 621 835 988 1123 1233 1239 1277 12771198440 115 279 376 574 651 818 888 857 770 746 834

TABLE 126 Tumor weight (g) Average Tumor ION No. weight (g) PBS 1.02 792169 0.85 1198728 0.88 1198440 0.36

Example 30 Activity of Modified Oligonucleotides Targeting Human Yap1 ina Human Hepatocellular Carcinoma SNU449 Xenograft Tumor Model

Modified oligonucleotides described in the studies above were tested ina hepatocellular carcinoma SNU449 xenograft tumor model. A controloligonucleotide 792169 was also tested.

Five million SNU449 cells in 30% matrigel were implanted subcutaneouslyinto the fatpads of female NOD.Cg-Prkdcscid II2rgtmlWjl/SzJ mice (fromJackson Laboratory) at 4-6 weeks of age. 43 days post implantation (whentumors had reached approximately 100 mm³ in size), groups of eight miceeach were administered with 50 mg/kg modified oligonucleotide daily for10 days (loading dose), following which they were administered with 50mg/kg modified oligonucleotide four times a week for one week, followingwhich they were dosed with 50 mg/kg modified oligonucleotide thriceweekly until the end of the study. Animals were sacrificed and tumorswere collected on day 119 post implantation. Yap1 mRNA knockdown intumors was measured by RT-qPCR as previously described using the HumanYap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to PBS treated animals (% control).

Tumor volumes were also measured at the indicated days in the tablebelow

TABLE 127 Yap1 mRNA levels in tumors Ion No. % control PBS 100  79216990 1198440 34

TABLE 128 Tumor volume (mm³) Days Post Average Tumor Volume Tumor (mm³)Implantation PBS 792169 1198440 43 111 111 111 46 175 162 152 50 208 180168 53 252 247 201 57 292 280 242 60 362 317 263 64 396 397 338 67 438466 376 71 463 519 373 75 570 559 401 78 597 634 429 81 657 681 514 85760 785 606 88 786 889 613 92 955 1170  690 94 1048 1215  773 98 11141355  804 101 1175 1417  818 105 1252 1509  894 108 1284 1571  921 1191431 1697* 978 *Average of 7 samples

Example 31 Activity of Modified Oligonucleotides Targeting Human Yap1 inNCI H747 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in colorectal adenocarcinoma cell line NCI H747. A controloligonucleotide 792169 was also tested.

RNA Analysis

Cultured NCI H747 cells at a density of 10,000 cells per well weretreated using free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 129 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in NCI H747 cells % UTC ION No. 0.04 μM 0.2 μM1 μM 5 μM 792169 94 83 87 100 715487 83 70 49 30 1198440 73 53 21 9Cell Proliferation Assay

Cultured NCI H747 cells at a density of 3000 cells/well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After 7 days, cellproliferation was measured using the luminescent cell viabilityCellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tablesbelow as percent control of the amount of luminescence in samplestreated with modified oligonucleotides relative to untreated controlcells (% UTC).

TABLE 130 Antiproliferative effect of modified oligonucleotides in NCIH747 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 89 97 91 80715487 91 86 65 42 1198440 87 66 36 18

Example 32 Activity of Modified Oligonucleotides Targeting Human Yap1 inNCI H292 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in mucoepidermoid pulmonary carcinoma cell line NCI1-1292. A control oligonucleotide 792169 was also tested.

RNA Analysis

Cultured NCI H292 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 131 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in NCI H292 cells % UTC ION No. 0.04 μM 0.2 μM1 μM 5 μM 792169 98 112 111 106 715487 104 83 40 12 1198440 89 53 18 5Cell Proliferation Assay

Cultured NCI H292 cells at a density of 1000 cells/well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 144hours, cell proliferation was measured using the luminescent cellviability CellTiter-Glo® 2.0 Assay (Promega). Results are presented inthe tables below as percent control of the amount of luminescence insamples treated with modified oligonucleotides relative to untreatedcontrol cells (% UTC).

TABLE 132 Antiproliferative effect of modified oligonucleotides in NCIH292 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 98 97 99 92715487 87 90 69 20 1198440 100 83 30 15

Example 33 Activity of Modified Oligonucleotides Targeting Human Yap1 inBICR56 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in squamous cell carcinoma adherent keratinocyte cell lineBICR56. A control oligonucleotide 792169 was also tested.

RNA Analysis

Cultured BICR56 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 133 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in BICR56 cells % UTC ION No. 0.04 μM 0.2 μM 1μM 5 μM 792169 99 92 85 97 715487 68 28 16 11 1198440 40 10 7 7Cell Proliferation Assay

Cultured BICR56 cells at a density of 1000 cells/well were treated usingfree uptake with modified oligonucleotides diluted to concentrationsdescribed in the tables below. After approximately 144 hours, cellproliferation was measured using the luminescent cell viabilityCellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tablesbelow as percent control of the amount of luminescence in samplestreated with modified oligonucleotides relative to untreated controlcells (% UTC).

TABLE 134 Antiproliferative effect of modified oligonucleotides inBICR56 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 106 100 92 87715487 70 26 9 4 1198440 28 10 6 4

Example 34 Effect of Modified Oligonucleotides Targeting Human Yap1 inCynomolgus Monkeys

Cynomolgus monkeys were treated with Ionis modified oligonucleotidesselected from studies described in the Examples above. Modifiedoligonucleotide tolerability was evaluated.

Treatment

Prior to the study, the monkeys were kept in quarantine during which theanimals were observed daily for general health. The monkeys were 2-4years old and weighed 2-4 kg. Eleven groups of 4 randomly assigned malecynomolgus monkeys each were injected subcutaneously with Ionisoligonucleotide or saline in a clock-wise rotation between fourdifferent sites on the back. Following loading doses on days 1, 3, 5 and7, the monkeys were dosed once per week (on days 14, 21, 28, 35, and 42)with 35 mg/kg of Ionis oligonucleotide. A control group of 4 cynomolgusmonkeys was injected with 0.9% saline in a similar manner and served asthe control group.

During the study period, the monkeys were observed twice daily for signsof illness or distress. Any animal experiencing more than momentary orslight pain or distress due to the treatment, injury or illness wastreated by the veterinary staff with approved analgesics or agents torelieve the pain after consultation with the Study Director. Any animalin poor health or in a possible moribund condition was identified forfurther monitoring and possible euthanasia. Scheduled euthanasia of theanimals was conducted on day 86 approximately 48 hours after the lastdose by exsanguination while under deep anesthesia. The protocolsdescribed in the Example were approved by the Institutional Animal Careand Use Committee (IACUC).

Body and Organ Weight Measurements

To evaluate the effect of Ionis oligonucleotides on the overall healthof the animals, body and organ weights were measured. Terminal bodyweight was measured prior to necropsy. Organ weights were measured aswell, and all weight measurements are presented in the Table below. Theresults indicate that effect of treatment with modified oligonucleotideson body and organ weights was within the expected range for modifiedoligonucleotides. Specifically, treatment with ION 1198440 was welltolerated in terms of the body and organ weights of the monkeys.

TABLE 135 Body and Organ weights (g) Terminal Body Liver with ION No.Weight Heart kidney spleen gallbladder Saline 2855 11 14 3 60  9584992894 10 15 4 68 1076453 2955 11 16 5 72 1197270 2852 10 17 4 73 11984392959 10 15 3 67 1198440 2919 11 15 3 65 1198605 2968 11 15 4 67 11986232790 9 13 3 62 1198728 2722 10 15 5 65 1198831 2788 11 14 4 65 11988723126 12 15 4 63Kidney and Liver Function

To evaluate the effect of Ionis oligonucleotides on hepatic and kidneyfunction, blood samples were collected from all the study groups on day44. The monkeys were fasted overnight prior to blood collection. Bloodwas collected in tubes without anticoagulant for serum separation. Thetubes were kept at room temperature for a minimum of 90 minutes and thencentrifuged at 3000 rpm for 10 minutes to obtain serum. Levels ofvarious liver function markers were measured using a Toshiba 200FR NEOchemistry analyzer (Toshiba Co., Japan). Plasma levels of glucose (GLU),blood urea nitrogen (BUN), creatinine (CREA), total protein (TP),albumin (ALB), globulin (GLO), albumin/globulin (A/G) ratio calculated,alanine aminotransferase (ALT), aspartate aminotransferase (AST), totalbilirubin (TBIL), gamma-glutamyltransferase (GGT), alkaline phosphatase(ALP), triglyceride (TG), high density lipoprotein (HDL), and lowdensity lipoprotein (LDL) were measured and the results are presented inthe table below. The results indicate that modified oligonucleotides hadno effect on liver function outside the expected range for modifiedoligonucleotides. Specifically, treatment with ION 1198440 was welltolerated in terms of the liver function in monkeys.

TABLE 136 Liver/Kidney function markers in cynomolgus monkey plasma ALTAST TBIL GGT ALP TG HDL LDL ION NO. (IU/L) (IU/L) (mg/dL) (IU/L) (IU/L)(mg/dL) (mg/dL) (mg/dL) Saline 60 50 0.3 91 1539 34 96 68  958499 67 730.2 67 1449 41 89 46 1076453 53 76 0.2 78 1173 29 98 66 1197270 84 780.2 75 1215 31 102 48 1198439 40 65 0.2 63 1298 28 82 59 1198440 45 750.2 80 1412 30 104 54 1198605 40 58 0.2 85 1445 25 115 57 1198623 50 470.2 59 916 34 87 50 1198728 58 92 0.3 59 1165 24 95 57 1198831 48 63 0.365 1096 22 108 63 1198872 48 94 0.3 79 1098 19 114 60

TABLE 137 Liver/Kidney function markers in cynomolgus monkey plasma GLUBUN CREA TP ALB GLO A/G ION NO. (mg/dL) (mg/dL) (mg/dL) (g/dL) (g/dL)(g/dL) ratio Saline 84 25 1.0 7.2 4.2 3.0 1.4  958499 83 24 0.9 7.2 4.03.2 1.3 1076453 89 27 0.9 7.0 3.9 3.1 1.3 1197270 115 27 0.9 6.8 3.7 3.11.2 1198439 115 24 0.9 6.8 4.0 2.8 1.4 1198440 91 26 0.9 7.0 4.1 2.9 1.41198605 69 22 0.8 6.7 4.0 2.7 1.5 1198623 70 26 0.8 7.2 4.2 3.0 1.41198728 95 26 0.9 7.3 4.1 3.2 1.3 1198831 73 26 0.7 6.7 3.9 2.8 1.41198872 80 27 0.9 7.1 4.0 3.1 1.3Pro-Inflammatory Proteins Analysis

To evaluate any inflammatory effect of Ionis oligonucleotides incynomolgus monkeys, blood samples were taken for analysis. The monkeyswere fasted overnight prior to blood collection. On day 42 (pre-dose and24 hours post-dose), approximately 0.8 mL of blood was collected fromeach animal and put into tubes without anticoagulant for serumseparation. The tubes were kept at room temperature for a minimum of 90min and then centrifuged at 3,000 rpm for 10 min at room temperature toobtain serum. Complement C3 were measured using a Toshiba 120 FR NEOchemistry analyzer (Toshiba Co., Japan). The results indicate thattreatment with ION 1198440 did not cause any inflammation in monkeys.Another marker of inflammation, C-Reactive Protein (CRP) was testedtogether with the clinical chemistry parameters tested for liverfunction above.

TABLE 138 Pro-inflammatory protein analysis in cynomolgus monkeysComplement C3 (mg/dL) Day 42 day 42 CRP (mg/L) ION No. (pre-dose) (24 hrpost-dose) day 44 Saline 117 106 4.1  958499 112 89 9.9 1076453 101 881.5 1197270 103 86 9.8 1198439 99 94 2.9 1198440 95 88 4.8 1198605 10595 4.2 1198623 105 101 2.0 1198728 93 90 4.0 1198831 81 81 1.1 1198872103 96 1.1Hematology

To evaluate any effect of Ionis oligonucleotides in cynomolgus monkeyson hematologic parameters, blood samples of approximately 0.5 mL ofblood was collected from each of the available study animals on day 44.The samples were collected in tubes containing K₂-EDTA. Samples wereanalyzed for red blood cell (RBC) count, Hemoglobin (HGB), Hematocrit(HCT), Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH),mean corpuscular hemoglobin concentration (MCHC), RBC Distribution Width(RCDW), reticulocyte count (Retic), platelet count (PLT), mean plateletvolume (MPV), white blood cells (WBC) count, individual white blood cellcounts, such as that of monocytes (MON), neutrophils (NEU), lymphocytes(LYM), eosinophils (EOS), basophils (BAS), and large unstained cells(LUC) using an ADVIA2120i hematology analyzer (Siemens, USA).

The data indicate the oligonucleotides did not cause any changes inhematologic parameters outside the expected range for modifiedoligonucleotides at this dose. Specifically, treatment with ION 1198440was well tolerated in terms of the hematologic parameters of themonkeys.

TABLE 139 Blood cell counts in cynomolgus monkeys RBC HGB HCT MCV MCHMCHC RCDW Retic PLT ION NO. (×10{circumflex over ( )}6/μL) (g/dL) (%)(fL) (pg) (g/dL) (%) (%) (10³/μL) Saline 5.8 13 46 79 23 29 13 1.2 334 958499 5.6 12 43 77 22 29 12 1.5 399 1076453 5.5 13 43 79 23 29 15 1.2358 1197270 5.6 12 44 79 22 28 12 1.1 452 1198439 6.0 14 48 79 22 28 121.2 367 1198440 5.9 14 47 80 23 29 12 1.2 420 1198605 6.1 13 46 75 22 2913 1.1 385 1198623 5.9 14 46 78 23 30 13 1.0 376 1198728 5.9 14 47 80 2329 12 1.3 428 1198831 5.6 13 43 76 23 30 12 1.0 377 1198872 5.7 13 44 7823 30 12 1.2 400

TABLE 140 Blood cell counts in cynomolgus monkeys WBC NEU LYM MON EOSBAS LUC MPV ION NO. (×10³/μL) (%) (%) (%) (%) (%) (%) (fL) ine 9.2 41 553.2 1.0 0.3 0.5 8.2  958499 12.0 49 44 3.5 1.1 0.4 1.2 7.6 1076453 10.039 54 3.9 1.1 0.4 1.2 8.4 1197270 10.6 38 54 3.5 2.7 0.4 1.2 7.1 119843910.3 27 68 2.9 1.5 0.3 0.6 7.6 1198440 10.9 28 65 3.2 2.8 0.4 0.7 7.51198605 10.5 44 51 2.8 0.8 0.4 0.5 8.1 1198623 11.7 43 53 2.0 0.8 0.40.7 7.8 1198728 10.7 29 64 2.9 2.2 0.5 0.9 8.0 1198831 7.6 44 50 3.3 2.00.3 0.8 7.3 1198872 10.4 64 32 2.2 0.6 0.3 0.5 7.1Coagulation

To evaluate effect of Ionis modified oligonucleotides on coagulation incynomolgus monkeys, blood samples of approximately 0.9 mL were collectedfrom each of the available study animals on day 44. The samples werecollected in tubes containing 3.2% sodium citrate. Coagulationparameters tested include Activated partial thromboplastin time (APTT),prothrombin time (PT) and Figrinogen (FIB).

The data indicate the modified oligonucleotides did not cause anychanges in coagulation parameters outside the expected range formodified oligonucleotides at this dose. Specifically, treatment with ION1198440 was well tolerated in terms of the coagulation parameters of themonkeys.

TABLE 141 Coagulation Parameters in cynomolgus monkeys PT FIB APTT IONNo. (sec) (mg/dL) (sec) Saline 9 229 18  958499 9 275 18 1076453 9 23420 1197270 10 257 17 1198439 10 246 19 1198440 10 260 20 1198605 9 23623 1198623 10 229 17 1198728 9 242 18 1198831 10 209 18 1198872 10 20621Urine Analysis

Food was removed overnight the day before fresh urine collection, butwater was supplied. Fresh urine samples for urinalysis and urinechemistry were collected from all animals using a clean cage pan on wetice (first in the morning) on day 44. Urinalysis/Urine Chemistryparameters creatinine (UCRE), microprotein (UTP), urine microalbumin(UALB), and protein/creatinine (P/C) ratio were measured using a Toshiba120FR automated chemistry analyzer (Toshiba Co., Japan). Specifically,treatment with ION 1198440 was well tolerated in terms urine chemistrymarkers.

TABLE 142 Urinalysis and Urine Chemistry Markers UTP UALB UCRE P/C IONNO. (mg/dL) (mg/dL) (mg/dL) ratio Saline 13 0.5 69 0.3  958499 16 0.1 600.3 1076453 14 0.1 50 0.3 1197270 18 1.3 56 0.3 1198439 15 0.1 68 0.21198440 13 0.2 53 0.3 1198605 12 0.4 69 0.2 1198623 10 0.2 44 0.21198728 16 0.3 70 0.2 1198831 13 0.1 46 0.3 1198872 14 0.3 111 0.2

Example 35 Activity of Modified Oligonucleotides Targeting Human Yap1 inBICR-22 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in tongue squamous carcinoma (lymph node metastasis) cellline BICR-22. A control oligonucleotide 792169, described herein above,was also tested.

RNA Analysis

Cultured BICR-22 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 144 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in BICR-22 cells % UTC ION No. 0.04 μM 0.2 μM1 μM 5 μM 792169 99 98 98 98 715487 82 45 23 13 1198440 44 14 4 4Cell Proliferation Assay

Cultured BICR-22 cells at a density of 1000 cells/well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 144hours, cell proliferation was measured using the luminescent cellviability CellTiter-Glo® 2.0 Assay (Promega). Results are presented inthe tables below as percent control of the amount of luminescence insamples treated with modified oligonucleotides relative to untreatedcontrol cells (% UTC).

TABLE 145 Antiproliferative effect of modified oligonucleotides inBICR-22 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 97 95 82 65715487 70 56 28 22 1198440 55 37 29 19

Example 36 Activity of Modified Oligonucleotides Targeting Human Yap1 inCAL33 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in tongue squamous cell carcinoma line CAL33. A controloligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured CAL33 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 146 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in CAL33 cells % UTC ION No. 0.04 μM 0.2 μM 1μM 5 μM 792169 106 106 91 85 715487 81 41 12 6 1198440 43 14 5 5Cell Proliferation Assay

Cultured CAL33 cells at a density of 1000 cells/well were treated usingfree uptake with modified oligonucleotides diluted to concentrationsdescribed in the tables below. After approximately 144 hours, cellproliferation was measured using the luminescent cell viabilityCellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tablesbelow as percent control of the amount of luminescence in samplestreated with modified oligonucleotides relative to untreated controlcells (% UTC).

TABLE 147 Antiproliferative effect of modified oligonucleotides in CAL33cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 92 93 81 67 71548789 79 61 37 1198440 84 67 58 44

Example 37 Activity of Modified Oligonucleotides Targeting Human Yap1 inCAL27 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in tongue squamous cell carcinoma line CAL27. A controloligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured CAL27 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 148 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in CAL27 cells % UTC ION No. 0.08 μM 0.4 μM 2μM 10 μM 792169 95 90 97 88 715487 35 23 5 3 1198440 23 6 4 4Cell Proliferation Assay

Cultured CAL27 cells at a density of 1000 cells/well were treated usingfree uptake with modified oligonucleotides diluted to concentrationsdescribed in the tables below. After approximately 144 hours, cellproliferation was measured using the luminescent cell viabilityCellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tablesbelow as percent control of the amount of luminescence in samplestreated with modified oligonucleotides relative to untreated controlcells (% UTC).

TABLE 149 Antiproliferative effect of modified oligonucleotides in CAL27cells % UTC ION No. 0.08 μM 0.4 μM 2 μM 10 μM 792169 96 102 103 90715487 95 85 67 33 1198440 86 85 83 51

Example 38 Activity of Modified Oligonucleotides Targeting Human Yap1 inDetroit-562 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in pharynx carcinoma cell line Detroit-562. A controloligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured Detroit-562 cells at a density of 5000 cells per well weretreated using free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 150 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in Detroit-562 cells % UTC ION No. 0.04 μM 0.2μM 1 μM 5 μM 792169 102 102 94 99 715487 77 29 10 5 1198440 32 8 3 2Cell Proliferation Assay

Cultured Detroit-562 cells at a density of 1000 cells/well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 144hours, cell proliferation was measured using the luminescent cellviability CellTiter-Glo® 2.0 Assay (Promega). Results are presented inthe tables below as percent control of the amount of luminescence insamples treated with modified oligonucleotides relative to untreatedcontrol cells (% UTC).

TABLE 151 Antiproliferative effect of modified oligonucleotides inDetroit-562 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 99 106100 79 715487 92 84 71 52 1198440 84 67 59 45

Example 39 Activity of Modified Oligonucleotides Targeting Human Yap1 inSCC-4 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in tongue squamous cell carcinoma cell line SCC 4. Acontrol oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SCC-4 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 152 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SCC-4 cells % UTC ION No. 0.04 μM 0.2 μM 1μM 5 μM 792169 92 106 105 104 715487 81 46 23 13 1198440 63 27 11 5Cell Proliferation Assay

Cultured SCC-4 cells at a density of 1000 cells/well were treated usingfree uptake with modified oligonucleotides diluted to concentrationsdescribed in the tables below. After approximately 144 hours, cellproliferation was measured using the luminescent cell viabilityCellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tablesbelow as percent control of the amount of luminescence in samplestreated with modified oligonucleotides relative to untreated controlcells (% UTC).

TABLE 153 Antiproliferative effect of modified oligonucleotides in SCC-4cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 125 169 142 136715487 158 121 106 69 1198440 82 60 21 11

Example 40 Activity of Modified Oligonucleotides Targeting Human Yap1 inSCC-9 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in tongue squamous cell carcinoma cell line SCC-9. Acontrol oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SCC-9 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 154 Dose-dependent inhibition of human Yap 1 mRNA expression bymodified oligonucleotides in SCC-9 cells % UTC ION No. 0.04 μM 0.2 μM 1μM 5 μM 792169 86 94 96 101 715487 74 44 21 11 1198440 53 18 6 2Cell Proliferation Assay

Cultured SCC-9 cells at a density of 1000 cells/well were treated usingfree uptake with modified oligonucleotides diluted to concentrationsdescribed in the tables below. After approximately 144 hours, cellproliferation was measured using the luminescent cell viabilityCellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tablesbelow as percent control of the amount of luminescence in samplestreated with modified oligonucleotides relative to untreated controlcells (% UTC).

TABLE 155 Antiproliferative effect of modified oligonucleotides in SCC-9cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 104 111 102 94715487 97 73 51 34 1198440 88 46 35 31

Example 41 Activity of Modified Oligonucleotides Targeting Human Yap1 inSCC-15 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in tongue squamous cell carcinoma cell line SCC-15. Acontrol oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SCC-15 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 156 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SCC-15 cells % UTC ION No. 0.04 μM 0.2 μM 1μM 5 μM 792169 91 100 102 105 715487 69 33 12 5 1198440 39 10 4 2Cell Proliferation Assay

Cultured SCC-15 cells at a density of 1000 cells/well were treated usingfree uptake with modified oligonucleotides diluted to concentrationsdescribed in the tables below. After approximately 144 hours, cellproliferation was measured using the luminescent cell viabilityCellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tablesbelow as percent control of the amount of luminescence in samplestreated with modified oligonucleotides relative to untreated controlcells (% UTC).

TABLE 157 Antiproliferative effect of modified oligonucleotides inSCC-15 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 93 92 89 71715487 87 66 47 28 1198440 72 54 42 32

Example 42 Activity of Modified Oligonucleotides Targeting Human Yap1 inSCC-25 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in tongue squamous cell carcinoma cell line SCC-25. Acontrol oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SCC-25 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 158 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SCC-25 cells % UTC ION No. 0.08 μM 0.4 μM 2μM 10 μM 792169 87 87 89 86 715487 70 32 16 11 1198440 32 12 8 7Cell Proliferation Assay

Cultured SCC-25 cells at a density of 1000 cells/well were treated usingfree uptake with modified oligonucleotides diluted to concentrationsdescribed in the tables below. After approximately 144 hours, cellproliferation was measured using the luminescent cell viabilityCellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tablesbelow as percent control of the amount of luminescence in samplestreated with modified oligonucleotides relative to untreated controlcells (% UTC).

TABLE 159 Antiproliferative effect of modified oligonucleotides inSCC-25 cells % UTC ION No. 0.08 μM 0.4 μM 2 μM 10 μM 792169 97 101 96 92715487 82 48 25 15 1198440 56 27 20 16

Example 43 Activity of Modified Oligonucleotides Targeting Human Yap1 inSNU-899 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in laryngeal squamous cell carcinoma cell line SNU-899. Acontrol oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SNU-899 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 160 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-899 cells % UTC ION No. 0.04 μM 0.2 μM1 μM 5 μM 792169 106 106 111 102 715487 62 26 9 4 1198440 35 12 3 2Cell Proliferation Assay

Cultured SNU-899 cells at a density of 1000 cells/well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 144hours, cell proliferation was measured using the luminescent cellviability CellTiter-Glo® 2.0 Assay (Promega). Results are presented inthe tables below as percent control of the amount of luminescence insamples treated with modified oligonucleotides relative to untreatedcontrol cells (% UTC).

TABLE 161 Antiproliferative effect of modified oligonucleotides inSNU-899 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 90 94 96 86715487 82 78 71 62 1198440 82 75 69 66

Example 44 Activity of Modified Oligonucleotides Targeting Human Yap1 inSNU-1066 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in laryngeal squamous cell carcinoma line SNU-1066. Acontrol oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SNU-1066 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 162 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-1066 cells % UTC ION No. 0.04 μM 0.2 μM1 μM 5 μM 792169 91 94 93 98 715487 77 49 22 7 1198440 70 28 7 2Cell Proliferation Assay

Cultured SNU-1066 cells at a density of 1000 cells/well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 144hours, cell proliferation was measured using the luminescent cellviability CellTiter-Glo® 2.0 Assay (Promega). Results are presented inthe tables below as percent control of the amount of luminescence insamples treated with modified oligonucleotides relative to untreatedcontrol cells (% UTC).

TABLE 163 Antiproliferative effect of modified oligonucleotides inSNU-1066 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 100 104 10296 715487 97 86 72 47 1198440 89 66 58 43

Example 45 Activity of Modified Oligonucleotides Targeting Human Yap1 inSNU-1076 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in upper aerodigestive tract/laryngeal squamous cellcarcinoma line SNU-1076. A control oligonucleotide 792169, describedherein above, was also tested.

RNA Analysis

Cultured SNU-1076 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 164 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-1076 cells % UTC ION No. 0.04 μM 0.2 μM1 μM 5 μM 792169 89 98 102 107 715487 89 67 31 11 1198440 83 43 11 3Cell Proliferation Assay

Cultured SNU-1076 cells at a density of 1000 cells/well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 144hours, cell proliferation was measured using the luminescent cellviability CellTiter-Glo® 2.0 Assay (Promega). Results are presented inthe tables below as percent control of the amount of luminescence insamples treated with modified oligonucleotides relative to untreatedcontrol cells (% UTC).

TABLE 165 Antiproliferative effect of modified oligonucleotides inSNU-1076 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 97 104 106108 715487 91 90 86 79 1198440 99 87 81 81

Example 46 Activity of Modified Oligonucleotides Targeting Human Yap1 inSNU-1214 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in laryngeal squamous cell carcinoma cell line SNU-12 4. Acontrol oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SNU-1214 cells at a density of 5000 cells per well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 166 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in SNU-1214 cells % UTC ION No. 0.04 μM 0.2 μM1 μM 5 μM 792169 97 104 106 109 715487 71 36 16 9 1198440 40 11 4 3Cell Proliferation Assay

Cultured SNU-1214 cells at a density of 1000 cells/well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 144hours, cell proliferation was measured using the luminescent cellviability CellTiter-Glo® 2.0 Assay (Promega). Results are presented inthe tables below as percent control of the amount of luminescence insamples treated with modified oligonucleotides relative to untreatedcontrol cells (% UTC).

TABLE 167 Antiproliferative effect of modified oligonucleotides inSNU-1214 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 105 90 9672 715487 93 69 52 38 1198440 84 72 53 49

Example 47 Activity of Modified Oligonucleotides Targeting Human Yap1 inUPCI:SCC090 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in tongue squamous cell carcinoma cell line UPCI:SCC090. Acontrol oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured UPCI:SCC090 cells at a density of 5000 cells per well weretreated using free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured as previously described using theHuman Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized toactin-beta content, as measured by primer probe set RTS5002. Results arepresented in the tables below as percent control of the amount of Yap1mRNA relative to untreated control cells (% UTC).

TABLE 168 Dose-dependent inhibition of human Yap1 mRNA expression bymodified oligonucleotides in UPCI:SCC090 cells % UTC ION No. 0.04 μM 0.2μM 1 μM 5 μM 792169 100 108 112 84 715487 70 37 26 14 1198440 60 26 10 5Cell Proliferation Assay

Cultured UPCI:SCC090 cells at a density of 1000 cells/well were treatedusing free uptake with modified oligonucleotides diluted toconcentrations described in the tables below. After approximately 144hours, cell proliferation was measured using the luminescent cellviability CellTiter-Glo® 2.0 Assay (Promega). Results are presented inthe tables below as percent control of the amount of luminescence insamples treated with modified oligonucleotides relative to untreatedcontrol cells (% UTC).

TABLE 169 Antiproliferative effect of modified oligonucleotides inUPCI:SCC090 cells % UTC ION No. 0.04 μM 0.2 μM 1 μM 5 μM 792169 100 10499 93 715487 92 94 72 68 1198440 101 92 75 70

Example 30 Activity of Modified Oligonucleotides Targeting Human Yap1 ina Human Hepatocellular Carcinoma SNU449 Xenograft Tumor Model (Alone andin Combination with Sorafenib)

Modified oligonucleotides described in the studies above were tested ina hepatocellular carcinoma SNU449 xenograft tumor model. In addition totesting the modified oligonucleotide by itself, combination therapy withsorafenib was also tested. A control oligonucleotide 792169, describedherein above, was also tested.

Five million SNU449 cells in 30% matrigel were implanted subcutaneouslyinto the fatpads of female NOD.Cg-Prkdcscid II2rgtmlWjl/SzJ mice (fromJackson Laboratory) at 4-6 weeks of age. 43 days post implantation (whentumors had reached approximately 100 mm³ in size), groups of eight miceeach were administered with 50 mg/kg modified oligonucleotide daily for10 days (loading dose), following which they were administered with 50mg/kg modified oligonucleotide four times a week for one week, followingwhich they were dosed with 50 mg/kg modified oligonucleotide thriceweekly until the end of the study. Another group of 8 animals wastreated with 30 mg/kg of sorafenib orally 7 times a week until end ofstudy. A final group of 8 animals were treated with a combination of 30mg/kg of sorafenib orally 7 times a week for 11 weeks and 50 mg/kg ofmodified oligonucleotide 1198440 at 50 mg/kg 5 times a week for 3 weeks,4 times a week for the following week, then 3 times a week for theduration of the study (7 weeks). Animals were sacrificed, and tumorswere collected on day 119 post implantation.

Measurement of RNA

Yap1 mRNA knockdown in tumors was measured by RT-qPCR as previouslydescribed using the Human Yap1 primer-probe set RTS4814. Yap1 mRNAlevels were normalized to actin-beta content, as measured by primerprobe set RTS5002. Results are presented in the tables below as percentcontrol of the amount of Yap1 mRNA relative to PBS treated animals (%control).

TABLE 127 Yap1 mRNA levels in tumors % Ion No. control PBS 100 792169 901198440 34 Sorafenib 103 1198440 + 42 SorafenibMeasurement of Tumor Volume

Tumor volumes were also measured at the indicated days in the tablebelow. Treatment with ION No. 1198440 led to significant reduction intumor volume. In addition, combination treatment of ION No. 1198440 withsorafenib led to further reduction in tumor volume.

TABLE 128 Tumor volume (mm³) Days Post Average Tumor Volume (mm³) Tumor1198440 + Implantation PBS 792169 1198440 sorafenib sorafenib 43 111 111111 112 111 46 175 162 152 145 162 50 208 180 168 159 162 53 252 247 201173 210 57 292 280 242 200 224 60 362 317 263 234 258 64 396 397 338 217210 67 438 466 376 277 250 71 463 519 373 249 241 75 570 559 401 283 27978 597 634 429 322 296 81 657 681 514 391 400 85 760 785 606 416 380 88786 889 613 451 413 92 955 1170  690 508 421 94 1048 1215  773 581 49598 1114 1355  804 625 525 101 1175 1417  818 685 541 105 1252 1509  894671 495 108 1284 1571  921 663 470 119 1431 1697* 978 747 584 *Averageof 7 samplesMeasurement of ERK Activation

Sorafenib is a RAF inhibitor used for treatment of several cancersincluding hepatocellular carcinoma. However, it leads to ERK activationin HCCs, which impacts therapeutic efficacy (Chen Y., et al., Overcomingsorafenib evasion in hepatocellular carcinoma using CXCR4-targetednanoparticles to co-deliver MEK-inhibitors, Sci Rep. 2017; 7: 44123).

The effect of modified oligonucleotide in mitigating the ERK1/2activation mediated by sorafenib was tested. Protein analysis wascarried out using standard procedures. The primary antibody againstErk1/2 was rabbit mAb 4695, Cell Signaling Technology, and againstpERK1/2 was rabbit anti-phospho p44/42 antibody 9101, Cell SignalingTechnology. ERK protein levels were compared to internal control GAPDH.GAPDH levels were measured using rabbit mAb 5174, Cell SignalingTechnology as the primary antibody. The secondary antibody used wasdonkey anti-rabbit NA934, GE Healthcare. pERK/ERK levels were calculatedrelative to PBS control to determine % activation of ERK1/2. Combinationtherapy of ION No. 1198440 with sorafenib led to a significant decreasein ERK1/2 activation mediated by sorafenib treatment alone.

TABLE 129 Tumor volume (mm³) % activation Ion No. of ERK1/2 PBS 100792169 100 1198440 88 Sorafenib 142 1198440 + 68 Sorafenib

Example 48 Activity of Modified Oligonucleotides Targeting Human Yap1 inCombination with Sorafenib in SNU449 Cells

Modified oligonucleotides described in the studies above were tested atvarious doses in hepatocellular carcinoma cell line SNU449. ION No.792169, described herein above, was used as a control modifiedoligonucleotide. ION No. 715487 was used to target Yap1 RNA. CulturedSNU449 cells at a density of 5000 cells per well were treated using freeuptake with modified oligonucleotides diluted to concentrationsdescribed in the tables below in combination with sorafenib diluted toconcentrations described in the tables below. After approximately 48hours, Yap1 mRNA levels were measured.

Measurement of RNA

Yap1 mRNA knockdown in tumors was measured by RT-qPCR as previouslydescribed using the Human Yap1 primer-probe set RTS4814. Yap1 mRNAlevels were normalized to actin-beta content, as measured by primerprobe set RTS5002. Results are presented in the tables below as percentcontrol of the amount of Yap1 mRNA relative to PBS treated cells (%control).

TABLE 170 Yap1 mRNA levels SORAFENIB YAP1 mRNA (% control) CONCENTRATION715487 715487 715487 715487 792169 792169 792169 792169 (uM) at 0.04 uMat 0.2 uM at 1 uM at 5 uM at 0.04 uM at 0.2 uM at 1 uM at 5 uM 0 98 5430 9 115 113 103 103 0.37 97 51 23 8 97 96 99 104 1.11 77 44 22 7 100 9793 95 3.33 83 45 21 7 99 91 92 97 10 78 46 20 8 102 94 93 97Cell Proliferation Assay

SNU449 plated at 1000 cells/well were treated with a combination ofmodified oligonucleotide and sorafenib at concentrations outlined in thetable below. 144 hours post treatment, proliferation of SNU449 cells wasmeasured using the luminescent cell viability CellTiter-Glo® 2.0 Assay(Promega). Results are presented in the tables below as percent controlof the amount of luminescence in samples treated with modifiedoligonucleotides relative to untreated control cells (% UTC).

TABLE 171 Antiproliferative effect of modified oligonucleotides inSNU449 cells SORAFENIB % UTC CONCENTRATION 715487 715487 715487 715487792169 792169 792169 792169 (uM) at 0.04 uM at 0.2 uM at 1 uM at 5 uM at0.04 uM at 0.2 uM at 1 uM at 5 uM 0 98 93 84 64 99 97 97 86 0.37 102 9483 64 103 100 95 84 1.11 93 77 45 23 97 91 89 68 3.33 27 12 5 3 51 30 276 10 2 2 1 1 3 4 3 1

Example 49 Activity of Modified Oligonucleotides Targeting Human Yap1 inCombination with a-PD1 Antibody in DEN-HCC Model

The DEN model is a chemically induced model of hepatocellular carcinoma(HCC). N-nitrosodiethylamine (DEN) is administered at 25 mg/kg into 15day old C57/BL6 mice. Carcinomas form 6 months post injection. Afterformation, carcinomas were then dissected from the liver and passagedsubcutaneously into C57BL/6 male mice at 4-6 weeks of age to establish asubcutaneous model. For this experiment, mice were passaged with P8subcutaneously established DEN carcinomas, rendering P9 for the durationof the experiment. Subcutaneous carcinomas are found to form at 4-6weeks post implantation. Modified oligonucleotides 792169 (controlcompound) and 715491 (YAP-1 targeting modified oligonucleotide) weretreated subcutaneously into groups of 7-8 mice at 10 mg/kg/week 5 timesa week for 11 weeks (total of 55 doses). The PBS-only treated group andthe control group were treated 5 times a week for 4 weeks (total of 20doses). α-PD1 antibody (BioXCell) was treated intraperitoneally at 10mg/kg/week twice a week for 4 weeks (total of 8 doses). Tumor volume wasmeasured over the time points indicated in the table below. F.D. refersto mice that were sacrificed because their tumor volume became toolarge. As shown in the table below, mice administered PBS, 792169(control compound), or α-PD1 antibody were sacrificed before the end ofthe experiment because their tumor volume became too large.

TABLE 172 Tumor volume (mm³) Average Tumor Volume (mm3) Days on 715491 +treatment PBS 792169 715491 α-PD1 α-PD1 1 373 354 356 546 455 5 553 376417 673 475 8 688 414 463 782 558 11 729 523 461 910 525 15 856 604 523911 529 18 968 633 526 1127 524 23 1220 773 658 1134 508 25 1337 864 6591252 513 28 1355 802 661 1412 489 31 F.D. F.D. 740 F.D. 516 35 F.D. F.D.798 F.D. 519 38 F.D. F.D. 741 F.D. 491 43 F.D. F.D. 723 F.D. 440 45 F.D.F.D. 741 F.D. 457 49 F.D. F.D. 765 F.D. 474 54 F.D. F.D. 780 F.D. 552 58F.D. F.D. 852 F.D. 544 61 F.D. F.D. 925 F.D. 592 65 F.D. F.D. 896 F.D.590 68 F.D. F.D. 940 F.D. 604 72 F.D. F.D. 953 F.D. 577 75 F.D. F.D. 985F.D. 675 79 F.D. F.D. 960 F.D. 590

What is claimed:
 1. A modified oligonucleotide according to thefollowing chemical structure:

or a salt thereof.
 2. A modified oligonucleotide according to thefollowing chemical structure:


3. A combination comprising the modified oligonucleotide of claim 1 anda secondary agent.
 4. The combination of claim 3, wherein the secondaryagent is a CDK4/6 inhibitor.
 5. The combination of claim 4, wherein theCDK4/6 inhibitor is palbociclib, ribociclib, or abemaciclib.
 6. Thecombination of claim 3, wherein the secondary agent is an EGFRinhibitor.
 7. The combination of claim 6, wherein the EGFR inhibitor iscetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib,osimertinib, gefitinib, lapatinib, or erlotinib.
 8. The combination ofclaim 3, wherein the secondary agent is a kinase inhibitor.
 9. Thecombination of claim 8, wherein the kinase inhibitor is sorafenib,regorafenib, or carbozantinib.
 10. A pharmaceutical composition,comprising the modified oligonucleotide of claim 1 and apharmaceutically acceptable diluent or carrier.
 11. A pharmaceuticalcomposition, comprising the modified oligonucleotide of claim 1 andwater.
 12. A pharmaceutical composition, comprising the modifiedoligonucleotide of claim 2 and a pharmaceutically acceptable diluent orcarrier.
 13. A pharmaceutical composition, comprising the modifiedoligonucleotide of claim 2 and water.
 14. An oligomeric compoundcomprising a modified oligonucleotide consisting of 16 linkednucleosides having the nucleobase sequence recited in SEQ ID NO: 2865,wherein the modified oligonucleotide has: a gap segment consisting often linked 2′-deoxynucleosides; a 5′ wing segment consisting of onelinked nucleoside; and a 3′ wing segment consisting of five linkednucleosides; wherein the gap segment is positioned between the 5′ wingsegment and the 3′ wing segment; wherein the 5′ wing segment comprises acEt nucleoside; wherein the 3′ wing segment comprises a cEt nucleoside,a 2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethylnucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein eachinternucleoside linkage is a phosphorothioate linkage; and wherein eachcytosine is a 5-methylcytosine.
 15. A pharmaceutical composition,comprising the oligomeric compound of claim 14 and a pharmaceuticallyacceptable diluent or carrier.
 16. A pharmaceutical composition,comprising the oligomeric compound of claim 14 and water.
 17. A methodof inhibiting expression of YAP1 in a cell, comprising contacting thecell with the oligomeric compound of claim 14, thereby inhibitingexpression of YAP1 in the cell.
 18. The method of claim 17, wherein thecell is a cancer cell.
 19. A method of inhibiting expression of YAP1 ina cell, comprising contacting the cell with the modified oligonucleotideof claim 1, thereby inhibiting expression of YAP1 in the cell.
 20. Themethod of claim 19, wherein the cell is a cancer cell.
 21. A method ofinhibiting expression of YAP1 in a cell, comprising contacting the cellwith the modified oligonucleotide of claim 2, thereby inhibitingexpression of YAP1 in the cell.
 22. The method of claim 21, wherein thecell is a cancer cell.
 23. The modified oligonucleotide of claim 1,which is the sodium salt or the potassium salt.